Heterocycle derivatives and their use for the treatment of cns disorders

ABSTRACT

The present application relates to novel heterocycle derivatives of Formula (I), to processes for preparing them, pharmaceutical compositions containing them, and their use thereof in the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer&#39; disease, cognitive disorders and/or memory deficits, as well as chronic and acute pain and other related CNS disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority from co-pendingU.S. provisional patent application No. 62/248,350 filed on Oct. 30,2015, the contents of which are incorporated herein by reference.

FIELD

The present application relates to novel heterocycle derivatives orcompounds, to processes for preparing them, pharmaceutical compositionscontaining them, and their use thereof, for example, in the treatment orprevention of acute and/or chronic neurological disorders such aspsychosis, epilepsy, schizophrenia, Alzheimer disease, cognitivedisorders and memory deficits, as well as chronic and acute pain andother related CNS disorders.

BACKGROUND

Epilepsy is a complex neurological disorder that affects ˜50 millionpeople worldwide. The lifetime prevalence is ˜1%, and it affectsindividuals of all ages regardless of gender or socio-economic status.Epilepsy can be acquired as a result of an insult to the brain such astrauma, infection, stroke or a tumour, or can result from a geneticmutation in one or more of the ion channel or neurotransmitter genes orproteins that control brain excitability (Bialer et al. Nat. Rev. DrugDiscov. 2010, 9:68-82).

Epileptic seizures can be generalized (generalized epileptic seizure),originating in both hemispheres of the brain simultaneously, or partial(focal seizures) originating in one or more parts of one or bothhemispheres, most commonly the temporal lobe. With generalized seizures,consciousness is always impaired or lost. Consciousness may bemaintained in partial seizures but partial seizures may becomegeneralized seizures in a process referred to as secondarygeneralization, at which point consciousness is lost. In patients thetype of epilepsy or epileptic syndrome are further classified accordingto features such as the type of seizure, etiology, age of onset andelectroencephalogram. Epilepsy or epileptic syndromes can be eitheridiopathic (etiology or cause is unknown) with a presumed genetic basisor symptomatic (acquired). The known potential causes of epilepsyinclude brain tumors, infections, traumatic head injuries, perinatalinsults, developmental malformations, cerebrovascular diseases, febrileseizures and status epilepticus (Loscher, Trends Pharmacol. Sci, 2002,23:113-118).

Despite progress in understanding the pathogenesis of epilepticseizures, the cellular basis of human epilepsy remains a mystery and, inthe absence of specific etiological comprehension, approaches to drugtherapy are still directed toward the control of symptoms, i.e.,suppression of seizures. Chronic administration of antiepileptic drugs(AEDs) is the treatment of choice in epilepsy (Dreyfuss et al. Handbookof Experimental Pharmacology; Springer: Berlin, 1999; 1-15).

The past decade witnessed considerable progress in the pharmacotherapyof epilepsy, including the introduction of several new AEDs and improvedformulations of older, “first-generation” drugs, such as phenytoin,carbamazepine, phenobarbital, and valproate. Newer “second-generation”drugs include lamotrigine, vigabatrin, tiagabine, topiramate,oxcarbazepine, zonisamide, gabapentin, and levetiracetam. However, onlya minority of patients refractory to first-generation AEDs are reportedto be seizure-free with second-generation AEDs.

A number of clinical anticonvulsants including phenytoin, carbamazepine,lamotrigine, gabapentin and pregabalin are widely utilized in themanagement of neuropathic pain (Collins et al. Expert Opinion EmergingDrugs, 2005, 10:95-108). Neuropathic pain results from a cascade ofneurobiological events, which tend to induce electrical hyperexcitability within somatosensory conduction pathway. Since electricalhyper excitability is also the hallmark of epileptic seizure activity,anticonvulsants are among the first agents adopted in the treatment ofneuropathic pain and remain the first option in clinical use.

Pain is both a sensory and emotional experience, and is generallyassociated with tissue damage or inflammation. Typically, pain isdivided into two general categories—acute pain and chronic pain. Bothdiffer in their etiology, pathophysiology, diagnosis, and mostimportantly treatment.

Acute pain is short term, and is typically of readily identifiablecause. Patients suffering from acute pain typically respond well tomedications. In contrast, chronic pain—medically defined as pain thatlasts for 3-6 months or longer, is often not associated with any obviousinjury; indeed, patients can suffer from protracted pain that persistsfor months or years after the initial insult. Whilst acute pain isgenerally favorably treated with medications, chronic pain is often muchmore difficult to treat, generally requiring expert care. Few, if any,ethical drugs have been prospectively developed for the treatment ofchronic pain. Instead, the current medications used to treat chronicpain are “borrowed” from other diseases, most commonly antiepilepticdrugs and antidepressants.

Current first-line treatments for chronic pain include opioids,analgesics such as gabapentin, and tricyclic antidepressants. Whenopioids are administered over prolonged periods, undesirable sideeffects such as drug tolerance, chemical dependency and evenphysiological addiction can occur. Of treatment remedies currentlyavailable for chronic pain, at best approximately 30% are effective insignificantly diminishing the pain, and these can lose their efficiencyover time.

In instances in which treatment with a single agent proves to beunsuccessful, combination therapy is often then explored as a secondline treatment. For example, such combination therapy may employadministration of an opioid agent with an adjuvant analgesic, althoughthe relative doses of each are often subject to prolonged trial anderror periods. Often, triple drug therapy is necessary. Such therapygenerally involves a combination of tricyclic antidepressants,anticonvulsants and a systemic local anesthetic. Patient compliancedrops significantly, however, when treatment requires the administrationof multiple pharmacologic agents. Recently, researchers reported the useof a combination of morphine and gabapentin in a randomized study forcontrolling nerve pain (Gilron, et al., N. Eng. J. Med., 2005,352:1281-82).

In treatment, it is important to consider overall pain relief, as wellas the type of pain relief. For example, chronic pain is typicallyviewed as allodynia or hyperalgesia. Allodynia is pain sensation from astimulus which is not normally painful. Allodynia is typically caused bya physical stimulus and is thus referred to as tactile or mechanicalallodynia. Hyperalgesia is an exaggerated sensation form a stimuluswhich is normally painful. The hyperalgesia can occur from a variety ofstimuli but, commonly, a patient's reaction to hot or cold stimuli isreported.

Neuropathic pain (NP) is generally thought of as a maladaptive chroniccondition in which pain originates from damaged nerves, often yieldingpain that is out of proportion to the extent of any injury. Damage canoccur from a physical injury such as trauma or from chemical injury suchas chemotherapeutics (e.g. paclitaxel). Neuropathic pain of this type isan important component of a number of syndromes of varying etiologieswhose common characteristic is the development of a prolonged andprofound pain state. Among these conditions are spinal cord injury,post-herpetic neuralgia, diabetic neuropathy, phantom limb pain,stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia, complexregional pain syndrome (CRPS), chemotherapy-induced neuropathic pain,vertebral disk rapture, trigeminal neuralgia and others.

Recently, it has been recognized that neuropathic pain can also manifestitself in the absence of an identifiable nerve injury. These indicationsinclude AIDS and mirror image pain. The lack of any nerve injury butunmistakable chronic pain has led to increased interest in the role ofglial cells in the maintenance of the neuropathic pain state (Watkinsand Maier, Drug Disc. Today: Ther. Strategies 2004, 1:83-88; Watkins andMaier, Nat. Rev. Drug Discovery 2003, 2:973-985). More specifically,recent research has demonstrated that glial cells enhance the release ofneurotransmitters which relay pain information to the spinal cord and,even more strikingly, release substances which increase the excitabilityof pain-responsive neurons in the spinal cord. These substances, calledpro-inflammatory cytokines, create and maintain exaggerated orpathological pain responses (Wieseler-Frank et al., Neurosignals 2005,14:166-174). Blocking the activation of glial cells reducespro-inflammatory cytokines and reverses pathological pain. To date, notherapeutics have been approved which have a putative glialcell-attenuation mechanism for the treatment of neuropathic pain.Molecules which are glial cell-attenuators may play an important role inthe treatment of neuropathic pain.

In light of the above shortcomings in current approaches for treatingchronic pain there exists a need for improved compositions and methodsfor treating pain, particularly neuropathic pain and its associatedsymptoms and, more specifically, neuropathic pain associated withcertain conditions such as fibromyalgia, among others. Such approachesshould ideally overcome one or more of the problems associated withexisting methods for treating chronic pain.

Migraine is a disease condition characterized by episodes of head painthat is often throbbing and frequently unilateral, and can be severe. Inmigraine without aura, attacks are usually associated with nausea,vomiting or sensitivity to light, sound or movement. In some patients,migraine attacks are usually preceded or accompanied by transient focalneurological symptoms, which are usually visual; such patients aredescribed as having migraine with aura.

Both migraine and epilepsy are usually included in the spectrum ofneurological chronic disorders with episodic manifestations that areknown to be characterized by recurrent attacks of nervous systemdysfunction with a return to baseline between attacks.

The hypothesis of a possible clinical continuum between migraine andepileptic syndromes as entities resulting from altered neuronalexcitability with a similar genetic basis has been postulated (Haut etal. Lancet Neurol 2006, 5:148-157). Epilepsy is a comorbid condition ofmigraine; it occurs more commonly in patients with migraine than in thegeneral population, and the prevalence of migraine in epileptic patientsis higher than in controls.

Some antiepileptic drugs (AEDs) are effective in the prevention ofmigraine (Rogawski et al Nat. Med. 2004, 10:685-692; Silberstein, S. D.,Trends Pharmacol. Sci. 2006, 27:410-415). A rationale for this use isthe hypothesis that migraine and epilepsy share several pathogeneticmechanisms.

Anxiety is broadly defined as a state of unwarranted or inappropriateworry often accompanied by restlessness, tension, distraction,irritability and sleep disturbances. This disproportionate response toenvironmental stimuli can hyper activate thehypothalamic-pituitary-adrenal axis and the autonomic nervous system,resulting in somatic manifestation of anxiety, including shortness ofbreath, sweating, nausea, rapid heartbeat and elevated blood pressure(Sanford et al. Pharmacol. Ther. 2000, 88:197-212). Anxiety disordersrepresent a range of conditions and as a result have been classifiedinto multiple distinct conditions, including generalized anxietydisorder (GAD), panic attack, post-traumatic stress disorder (PTSD),obsessive compulsive disorder (OCD) and social phobias (Sanford et al.Acta. Psychiatr. Scand. Suppl. 1998, 393:74-80).

Generalized anxiety disorder (GAD) is the most common of the anxietydisorders and is characterized by excessive and persistent worries. Someof the specific symptoms of GAD include restlessness, motor tension,difficulty concentrating, irritability, and sleep disturbances and theseverity of the symptoms over time may be linked to the changing natureof the environmental stressor. With age, GAD symptoms become lesssevere.

Panic Disorder is a well-studied psychiatric condition that consists ofmultiple disabling panic attacks characterized by and intense autonomicarousal. In addition, heightened fear and anxiety states occur bothduring and between panic attacks. Approximately 3% of woman and 1.5% ofmen have panic attacks. During a panic attack, the individualexperiences multiple symptoms including light-headedness, a poundingheart and difficulty in breathing. Panic disorder may be caused by anoversensitive brain system regulating autonomic functions.

Post-traumatic stress disorder (PTSD) is another example of a disorderassociated with intense fear and anxiety states that require psychiatrictreatment. PTSD results from exposure to a life threatening or traumaticevent. Individuals with PTSD have recurring thoughts of the terrifyingevent. Reenactment of the event varies in duration from a few seconds orhours to several days. Individuals with major depression, with panicdisorders or lacking strong social supports are vulnerable to developPTSD.

Anxiety disorders, which occur in 10% to 30% of the population,represent not only a significant public health issue but place asubstantial economic burden on society. A number of drugs have eitherbeen developed or are being developed for treating the differentsubclasses of anxiety. Some of these agents such as tricyclicantidepressants and β-adrenoreceptor antagonists found either limiteduse in treating specific disorders such as performance anxiety (e.g.β-adrenoreceptor antagonists suppression of the sympatheticmanifestations of anxiety) or have fallen out of favor for reasons ofefficacy and/or safety. Currently, direct and indirect serotoninreceptor agonists (e.g. selective serotonin reuptake inhibitors (SSRI)and buspirone) and benzodiazepines are most often prescribed fortreating anxiety disorders with benzodiazepine receptor agonist being apreferred therapeutic modality. The ability of benzodiazepines toenhance γ-aminobutyric acid (GABA) neurotransmission safely and rapidlyis central to their effectiveness in treating anxiety disorderespecially GAD and panic disorders (Stahl et al. J. Clin. Psychiatry2002, 63: 756-757). Benzodiazepines act by positively modulating theinhibitory neurotransmitter GABA through an allosteric site on the GABAA receptor complex, a ligand-gated chloride ion channel. Nonetheless,the use of benzodiazepines is limited by side effects associated withenhanced GABAnergic neurotransmission, manifesting as sedation, musclerelaxation, amnesia and ataxia. Moreover, the potential for abuse andphysical dependence is associated with the long-term use ofbenzodiazepines.

The following compound was reported to be active in the mouseelectroshock seizure (MES) and pentylenetetrazole (PTZ) models ofepilepsy (Bioorg. Med. Chem 2006; 14 (20), 6868; Eur. J. Med. Chem 2009;44 (3), 1265):

SUMMARY

The compounds of this application were strategically designed with theobjective of identifying a broad spectrum antiepileptic drug (AED) witha favorable safety and tolerability profile. A broad spectrum profilecould distinguish these compounds not only from other first-generationAED such as phenytoin (PHT) and carbamazepine (CBZ) but also from manyof the second-generation compounds such as pregabalin and levetiracetam.In preclinical studies, compounds that demonstrate broad anticonvulsantactivity in acute rodent seizure models of electroshock and chemicalorigin (e.g. MES and PTZ) may show efficacy in suppressing spike andwave discharges in models of generalized absence epilepsy. Furthermore,the compounds of this application were designed to have potentialtherapeutic applications beyond epilepsy.

The present application relates to novel heterocycle derivatives orcompounds, to processes for preparing them, pharmaceutical compositionscontaining them, and uses thereof in the treatment or prevention ofacute and/or chronic neurological disorders such as psychosis, epilepsy,schizophrenia, Alzheimer' disease, cognitive disorders and memorydeficits, as well as chronic and acute pain and other related CNSdisorders.

It is an object of the present application to provide compounds andcompositions useful for the treatment of a CNS disorder such asepilepsy, pain, or an anxiety disorder.

In one aspect, there is provided a compound of Formula (I), or apharmaceutically acceptable salt, solvate, tautomer or optical isomer,or combination thereof:

wherein:R₁ is selected from the group consisting of C₁-C₆ lower alkyl, C₁-C₆lower alkoxy, C₁-C₆ lower alkyl-ester, C₁-C₆ lower alkyl-amide, C₁-C₆lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆-lower haloalkoxy,C₁-C₆-lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl,alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl,alkynyl, aryl-alkynyl, cycloalkenyl, heterocycloalkenyl,alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,and alkylene-O-alkylene-cycloalkyl,alkylene-O-alkylene-heterocycloalkyl, each R₁ group being optionallysubstituted with one or more independently-selected groups R₅;R₂ and R₃ are each independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; orR₂ and R₃ connect to form, together with the carbon atom to which theyare attached, a three to seven-membered carbocyclic or heterocyclicring; andR₄ is selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;X and Q are independently selected from CH₂, O, NR₇, S, SO and SO₂;R₅ is selected from the group consisting of hydroxy, halogen, cyano,nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂, C₁-C₆ lower alkyl,C₁-C₆ lower alkoxy, C₁-C₆ lower alkyl-ester, C₁-C₆ lower alkyl-amide,C₁-C₆ lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆ lower haloalkoxy,C₁-C₆ lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl,heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl,alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,alkylene-O-alkylene-cycloalkyl and alkylene-O-alkylene-heterocycloalkyl;andR₆ and R₇ are independently selected from the group consisting of H,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl,provided that at least one of R₁, R₂ and R₃ comprises a fluorine atom.

In some embodiments, the present application includes a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, tautomer oroptical isomer, or combination thereof:

wherein:R₁ is selected from the group consisting of C₁-C₆alkyl, C₁-C₆cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene-aryl,C₁-C₆alkylene-heteroaryl, C₂-C₆alkenyl, C₂-C₆alkenylenearyl,C₂-C₆alkenyleneheteroaryl, C₂-C₆alkynyl, C₂-C₆alkynylene-aryl,C₃-C₁₂cycloalkenyl, heterocycloalkenyl, C₁-C₆alkylene-O—C₁-C₆alkyl,C₁-C₆alkylene-O—C₃-C₁₂cycloalkyl, C₁-C₆alkylene-O-heterocycloalkyl,C₁-C₆alkylene-O—C₁-C₆alkylene-C₃-C₁₂cycloalkyl andC₁-C₆alkylene-O—C₁-C₆alkylene-heterocycloalkyl, each R₁ group beingoptionally substituted with one or more independently-selected groupsR₅;R₂ and R₃ are each independently selected from the group consisting ofhydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₃-C₁₂cycloalkyl, heterocycloalkyl, aryl and heteroaryl;orR₂ and R₃ connect to form, together with the carbon atom to which theyare attached, a three to seven-membered carbocyclic or heterocyclicring; andR₄ is selected from the group consisting of hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₃-C₁₂cycloalkyl,heterocycloalkyl, aryl and heteroaryl;X and Q are independently selected from CH₂, O, NR₇, S, SO and SO₂;R₅ is selected from the group consisting of hydroxy, halogen, cyano,nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkyl-ester, C₁-C₆alkyl-amide, C₁-C₆alkyl-acid,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆haloalkyl-ester, C₃-C₁₂cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆hydroxyalkyl,C₃-C₁₂hydroxycycloalkyl, hydroxy-heterocycloalkyl, C₁-C₆cyanoalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₂cycloalkenyl, heterocycloalkenyl,C₁-C₆alkylenearyl, C₁-C₆alkyleneheteroaryl, C₁-C₆alkylene-O—C₁-C₆alkyl,C₁-C₆alkylene-O—C₃-C₁₂cycloalkyl, C₁-C₆alkylene-O-heterocycloalkyl,C₁-C₆alkylene-O—C₁-C₆alkylene-C₃-C₁₂cycloalkyl andC₁-C₆alkylene-O—C₁-C₆alkylene-heterocycloalkyl; andR₆ and R₇ are independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₃-C₁₂cycloalkyl, heterocycloalkyl, aryl and heteroaryl,provided that at least one of R₁, R₂ and R₃ comprises a fluorine atom.

In some embodiments, R₁ comprises a difluoromethoxy or atrifluoromethoxy substituent. In some embodiments, R₂ and R₃ are both H.

In one aspect, there is provided a compound of Formula (I):

wherein:R₁ is selected from the group consisting of C₁-C₆-lower alkyl,C₁-C₆-lower alkoxy, C₁-C₆-lower alkyl-ester, C₁-C₆-lower alkyl-amide,C₁-C₆-lower alkyl-acid, C₁-C₆-lower haloalkyl, C₁-C₆-lower haloalkoxy,C₁-C₆-lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl,hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, alkenyl,aryl-alkenyl, heteroaryl-alkenyl, alkynyl, aryl-alkynyl,heteroary-alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, alkylaryl, alkylheteroaryl, alkylene-O-alkyl,alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl,optionally substituted with one or more independently-selected groupsR₅; wherein R₅ selected from the group consisting of H, hydroxy,halogen, cyano, nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂,C₁-C₆-lower alkyl, C₁-C₆-lower alkoxy, C₁-C₆-lower alkyl-ester,C₁-C₆-lower alkyl-amide, C₁-C₆-lower alkyl-acid C₁- to C₆-lowerhaloalkyl, C₁-C₆-lower haloalkoxy, C₁-C₆-lower haloalkyl-ester,cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl,heteroaryl, aryl, hetero-aryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkylaryl,alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl,alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl,alkylene-O-alkylene-heterocycloalkyl;R₂ and R₃ are each independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; orR₂ and R₃ connect to form a three to seven-membered ring; andR₄ is selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; andX and Q are independently selected from C, O, NR₇, S, SO and SO₂,wherein R₇ is selected from the groups consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In another aspect, R₁ is optionally substituted with one or moreindependently-selected groups R₈ and R₈ is selected from the groupconsisting of OH, CN, halo, alkyl, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, heterocycloalkyl, C(O)R₇, C(O)OR₉, SO₂R₉ and C(O)NR₁₀R₁₁;wherein R₉, R₁₀ and R₁₁ are independently selected from the groupconsisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl. In yet a further aspect, R₂ and R₃ are independentlyselected from the group consisting of H, halogen, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, and substituted or unsubstitutedheterocycloalkyl.

In a specific aspect, R₁ is a substituted alkyl-aryl oralkyl-heteroaryl, and R₂ and R₃ are independently selected fromhydrogen, halogen or lower alkyl, and R₄ is selected from hydrogen andlower alkyl.

In a more specific aspect, R₁ is substituted with one or moreindependently-selected groups R₆, wherein R₆ is selected from halo andhaloalkyl, and R₄ is hydrogen.

In yet another aspect, there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one pharmaceuticallyacceptable carrier and/or excipient. In a further aspect, the carrier isa pharmaceutically-acceptable carrier.

In another aspect, there is provided a pharmaceutical compositioncomprising therapeutically effective amount of a compound of Formula (I)to treat medical conditions such as epilepsy, neuropathic pain, acuteand chronic inflammatory pain, migraine, tardive dyskinesia, anxiety andother related CNS disorders; such compositions can comprise a compoundof Formula (I) in association with one or more pharmaceuticallyacceptable diluents, excipients and/or inert carriers.

In yet another aspect there is provided a method for treating at leastone of epilepsy, neuropathic pain, acute and chronic inflammatory pain,migraine, tardive dyskinesia, anxiety and other related CNS disorders ina mammal, comprising administering to the mammal a therapeuticallyeffective amount of a compound or composition noted above. In a furtheraspect, the mammal is a human. In still a further aspect, the compoundor composition is administered orally and/or parenterally. In yetanother aspect, the compound or composition is administeredintravenously and/or intraperitoneally.

In yet a further aspect there is provided the use of the compound orcomposition noted above for manufacture of a medicament for treatment ofat least one of epilepsy, neuropathic pain, acute and chronicinflammatory pain, migraine, tardive dyskinesia, anxiety and otherrelated CNS disorders. In yet a further aspect there is provided the useof the compound or composition noted above for treatment of at least oneof epilepsy, neuropathic pain, acute and chronic inflammatory pain,migraine, tardive dyskinesia, anxiety and other related CNS disorders ina mammal. In a further aspect, the mammal is a human. In still a furtheraspect, the compound or composition is administrable orally and/orparenterally. In yet another aspect, the compound or composition isadministrable intravenously and/or intraperitoneally.

In another aspect, there is provided use of the compound of Formula (I)in the treatment of epilepsy, neuropathic pain, acute and chronicinflammatory pain, migraine, tardive dyskinesia, anxiety and otherrelated CNS disorders.

The application additionally provides a process for the preparation ofcompounds of Formula (I). General and specific processes are discussedin more detail set forth in the Examples below.

Other features and advantages of the present application will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating embodiments of the application, are given byway of illustration only and the scope of the claims should not belimited by these embodiments, but should be given the broadestinterpretation consistent with the description as a whole.

DRAWINGS

The embodiments of the application will now be described in greaterdetail with reference to the attached drawings in which:

FIG. 1 shows the effect of compound 3 in an Intravenous Metrazol SeizureThreshold Test in a mouse.

FIG. 2 shows the effect of compound 3 on Hippocampal ParoxysmalDischarges (HPD) in Mice 4 Weeks after Unilateral Intra-hippocampal KAInjection.

DETAILED DESCRIPTION I. Definitions

Unless otherwise indicated, the definitions and embodiments described inthis and other sections are intended to be applicable to all embodimentsand aspects of the present application herein described for which theyare suitable as would be understood by a person skilled in the art.

Unless specified otherwise within this specification, the nomenclatureused in this specification generally follows the examples and rulesstated in “Nomenclature of Organic chemistry” (Pergamon Press, 1979),Sections A, B, C, D, E, F, and H. Optionally, a name of a compound maybe generated using a chemical naming program: ACD/ChemSketch, Version5.09/September 2001, Advanced Chemistry Development, Inc., Toronto,Canada.

The term “C_(m)-C_(n)” or “C_(m)-C_(n) group” used alone or as a prefix,refers to any group having m to n carbon atoms, wherein m and n are 0 orpositive integers, and n>m. For example, “C₁-C₆” would refer to achemical group having 1 to 6 carbon atoms.

The term “group” and “radical” are used interchangeably herein.

The term “hydrocarbon” used alone or as a suffix or prefix, refers toany structure comprising only carbon and hydrogen atoms up to 14 carbonatoms.

The term “hydrocarbon radical” or “hydrocarbyl” used alone or as asuffix or prefix, refers to any structure as a result of removing one ormore hydrogens from a hydrocarbon.

The term “alkyl” used alone or as a suffix or prefix, refers tomonovalent straight or branched chain hydrocarbon radicals comprising 1to about 12 carbon atoms. The term “lower alkyl” as used herein refersto an alkyl group having 1 to 6 carbon atoms.

The term “alkylene” used alone or as suffix or prefix, refers todivalent straight or branched chain hydrocarbon radicals comprising 1 toabout 12 carbon atoms, which serves to links two structures together.

The term “alkenyl” used alone or as suffix or prefix, refers to amonovalent straight or branched chain hydrocarbon radical having atleast one carbon-carbon double bond and comprising at least 2 up toabout 12 carbon atoms.

The term “alkynyl” used alone or as suffix or prefix, refers to amonovalent straight or branched chain hydrocarbon radical having atleast one carbon-carbon triple bond and comprising at least 2 up toabout 12 carbon atoms.

The term “cycloalkyl,” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical comprising at least 3 upto about 12 carbon atoms.

The term “cycloalkenyl” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical having at least onecarbon-carbon double bond and comprising at least 3 up to about 12carbon atoms.

The term “cycloalkynyl” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical having at least onecarbon-carbon triple bond and comprising about 7 up to about 12 carbonatoms.

The term “aryl” used alone or as suffix or prefix, refers to amonovalent hydrocarbon radical having one or more polyunsaturated carbonrings having aromatic character, (e.g., 4n+2 delocalized electrons) andcomprising 5 up to about 14 carbon atoms.

The term “arylene” used alone or as suffix or prefix, refers to adivalent hydrocarbon radical having one or more polyunsaturated carbonrings having aromatic character, (e.g., 4n+2 delocalized electrons) andcomprising 5 up to about 14 carbon atoms, which serves to links twostructures together.

The term “heterocycle,” used alone or as a suffix or prefix, refers to aring-containing structure or molecule having one or more multivalentheteroatoms, independently selected from N, O and S, as a part of thering structure and including at least 3 and up to about 20 atoms in thering(s). Heterocycle may be saturated or unsaturated, containing one ormore double bonds, and heterocycle may contain more than one ring. Whena heterocycle contains more than one ring, the rings may be fused orunfused. Fused rings generally refer to at least two rings share twoatoms therebetween. Heterocycle may have aromatic character or may nothave aromatic character.

The term “heteroalkyl,” used alone or as a suffix or prefix, refers to aradical formed as a result of replacing one or more carbon atom of analkyl with one or more heteroatoms selected from N, O and S.

The term “heteroaromatic,” used alone or as a suffix or prefix, refersto a ring-containing structure or molecule having one or moremultivalent heteroatoms, independently selected from N, O and S, as apart of the ring structure and including at least 3 and up to about 20atoms in the ring(s), wherein the ring-containing structure or moleculehas an aromatic character (e.g., 4n+2 delocalized electrons).

The term “heterocyclic group,” “heterocyclic moiety,” “heterocyclic,” or“heterocyclo” used alone or as a suffix or prefix, refers to a radicalderived from a heterocycle by removing one or more hydrogens therefrom.

The term “heterocyclyl” used alone or as a suffix or prefix, refers to amonovalent radical derived from a heterocycle by removing one hydrogentherefrom.

The term “heterocyclylene” used alone or as a suffix or prefix, refersto a divalent radical derived from a heterocycle by removing twohydrogens therefrom, which serves to links two structures together.

The term “heteroaryl” used alone or as a suffix or prefix, refers to aheterocyclyl having aromatic character.

The term “heterocylcoalkyl” used alone or as a suffix or prefix, refersto a heterocyclyl that does not have aromatic character.

The term “heteroarylene” used alone or as a suffix or prefix, refers toa heterocyclylene having aromatic character.

The term “heterocycloalkylene” used alone or as a suffix or prefix,refers to a heterocyclylene that does not have aromatic character.

The term “six-membered” used as prefix refers to a group having a ringthat contains six ring atoms.

The term “five-membered” used as prefix refers to a group having a ringthat contains five ring atoms.

A five-membered ring heteroaryl is a heteroaryl with a ring having fivering atoms, where 1, 2 or 3 ring atoms are independently selected fromN, O and S.

Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having sixring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As a prefix, “substituted” refers to a structure, molecule or group inwhich one or more hydrogens are replaced with one or moreC₁₋₁₂hydrocarbon groups or with one or more chemical groups that containone or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.Exemplary chemical groups containing one or more heteroatoms includeheterocyclyl, —NO₂, —OR, —R′OR, —CI, —Br, —I, —F, —CF₃, —C(═O)R,—C(═O)OH, —NH₂, —SH, —NHR, —NR₂, —SR, —SO₃H, —SO₂R, —S(═O)R, —CN, —OH,—C(═O)OR, —C(═O)NR₂, —NRC(═O)R, —NRC(═O)OR, —R′NR₂, oxo (═O), imino(═NR), thio (═S), and oximino (═N—OR), wherein each “R” is hydrogen or aC₁₋₁₂hydrocarbyl and “R′” is a C₁₋₁₂hydrocarbyl. For example,substituted phenyl may refer to nitrophenyl, pyridylphenyl,methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro,pyridyl, methoxy, chloro, and amino groups may replace any suitablehydrogen on the phenyl ring.

As a suffix, “substituted” used in relation to a first structure,molecule or group, followed by one or more names of chemical groups,refers to a second structure, molecule or group that results fromreplacing one or more hydrogens of the first structure, molecule orgroup with the one or more named chemical groups. Thus, a “phenylsubstituted by nitro” refers to nitrophenyl.

The term “optionally substituted” refers to groups, structures, ormolecules that are either substituted or not substituted.

It is understood that substituents and substitution patterns on thecompounds of the application may be selected by one of ordinary skill inthe art to provide compounds that are chemically stable and that can bereadily synthesized by techniques known in the art, as well as thosemethods set forth below. If a substituent is itself substituted withmore than one group, it is understood that these multiple groups may beon the same carbon or on different carbons, as long as a stablestructure results.

Heterocycle includes, for example, monocyclic heterocycles such as:aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran,1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine,2,3,4,7-tetrahydro-1H-azepine homopiperazine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles, for example,pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan,pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole,1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole,1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole,1,3,4-thiadiazole, and 1,3,4-oxadiazole.

Additionally, heterocycle encompass polycyclic heterocycles, forexample, indole, indoline, isoindoline, quinoline, tetrahydroquinoline,isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin,dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran,chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene,indolizine, isoindole, indazole, purine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine,perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine,1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole,benzimidazole, benztriazole, thioxanthine, carbazole, carboline,acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycleincludes polycyclic heterocycles wherein the ring fusion between two ormore rings includes more than one bond common to both rings and morethan two atoms common to both rings. Examples of such bridgedheterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and7-oxabicyclo[2.2.1]heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as:aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl,dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl,tetrahydrofuranyl, thiophanyl, piperidinyl,1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl,1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl,homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl,1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl,for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls(including both aromatic or non-aromatic), for example, indolyl,indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl,dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl,isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl,phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl,purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl,benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl,pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above,heterocyclyl includes polycyclic heterocyclyls wherein the ring fusionbetween two or more rings includes more than one bond common to bothrings and more than two atoms common to both rings. Examples of suchbridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl;and 7-oxabicyclo[2.2.1]heptyl.

The term “alkoxy,” used alone or as a suffix or prefix, refers toradicals of the general formula —O—R, wherein R is selected from ahydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy,and propargyloxy.

The term “amine” or “amino,” used alone or as a suffix or prefix, refersto radicals of the general formula —NRR′, wherein R and R′ areindependently selected from hydrogen or a hydrocarbon radical.

Used alone or as a prefix or suffix, “acyl” means the group —C(═O)—R,wherein R is an optionally substituted hydrocarbyl, hydrogen, amino oralkoxy. Acyl groups include, for example, acetyl, propionyl, benzoyl,phenyl acetyl, carboethoxy, and dimethylcarbamoyl.

The term “C₁-C₆-lower alkyl-ester” as used herein means the groupC₁-C₆alkylene-C(═O)—OR, wherein R is an optionally substitutedhydrocarbyl.

The term “C₁-C₆-lower alkyl-amide” as used herein means the groupC₁-C₆alkylene-C(═O)—NRR′, wherein R and R′ are independently, H or anoptionally substituted hydrocarbyl.

The term “C₁-C₆-lower alkyl-acid” as used herein means the groupC₁-C₆alkylene-C(═O)—OH.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“Halogenated,” used as a prefix of a group, means one or more hydrogenson the group is replaced with one or more halogens.

A first ring group being “fused” with a second ring group means thefirst ring and the second ring share at least two atoms there between.

“Link,” “linked,” or “linking,” unless otherwise specified, meanscovalently linked or bonded.

The term “compound(s) of the application” or “compound(s) of the presentapplication” as used herein means a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, isoform, tautomer,optical isomer, or combination thereof.

The term “composition(s) of the application” or “composition(s) of thepresent application” as used herein means a composition comprising atleast one compound of the application and at least one an additionalcomponent, such as a carrier.

The term “pharmaceutically acceptable salt” means either an acidaddition salt or a basic addition salt which is compatible with thetreatment of patients.

A “pharmaceutically acceptable acid addition salt” is any non-toxicorganic or inorganic acid addition salt of the base compoundsrepresented by Formula (I) or any of its intermediates. Illustrativeinorganic acids which form suitable salts include hydrochloric,hydrobromic, sulfuric and phosphoric acid and acid metal salts such assodium monohydrogen orthophosphate and potassium hydrogen sulfate.Illustrative organic acids which form suitable salts include the mono-,di- and tricarboxylic acids. Illustrative of such acids are, forexample, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic,benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic,2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids suchas methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either themono- or di-acid salts can be formed, or such salts can exist in eithera hydrated, solvated or substantially anhydrous form. In general, theacid addition salts of these compounds are more soluble in water andvarious hydrophilic organic solvents, and generally demonstrate highermelting points in comparison to their free base forms. The selectioncriteria for the appropriate salt will be known to one skilled in theart. Other non-pharmaceutically acceptable salts e.g. oxalates may beused for example in the isolation of compounds of Formula (I) forlaboratory use, or for subsequent conversion to a pharmaceuticallyacceptable acid addition salt.

A “pharmaceutically acceptable basic addition salt” is any non-toxicorganic or inorganic base addition salt of the acid compoundsrepresented by Formula (I) or any of its intermediates. Illustrativeinorganic bases which form suitable salts include lithium, sodium,potassium, calcium, magnesium or barium hydroxides. Illustrative organicbases which form suitable salts include aliphatic, alicyclic or aromaticorganic amines such as methylamine, trimethyl amine and picoline orammonia. The selection of the appropriate salt may be important so thatester functionality, if any, elsewhere in the molecule is nothydrolyzed. The selection criteria for the appropriate salt will beknown to one skilled in the art.

“Solvate” means a compound of Formula (I) or the pharmaceuticallyacceptable salt of a compound of Formula (I) wherein molecules of asuitable solvent are incorporated in a crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered as thesolvate. Examples of suitable solvents are ethanol, water and the like.When water is the solvent, the molecule is referred to as a hydrate.

The term “stereoisomers” is a general term for all isomers of theindividual molecules that differ only in the orientation of their atomsin space. It includes mirror image isomers (enantiomers), geometric(cis/trans) isomers and isomers of compounds with more than one chiralcenter that are not mirror images of one another (diastereomers).

“Patient” for the purposes of the present application includes humansand other animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In an embodiment the patient is a mammal, and in a anotherembodiment the patient is human.

“Therapeutically effective amount” is an amount of a compound of theapplication, that when administered to a patient, ameliorates a symptomof the disease. The amount of a compound of the application whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the disease state and its severity, the age of the patientto be treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

The term “treat” or “treating” means to alleviate symptoms, eliminatethe causation of the symptoms either on a temporary or permanent basis,or to prevent or slow the appearance of symptoms of the named disorderor condition.

The term “therapeutically effective amount” means an amount of thecompound of the application, such as the compound of Formula (I), whichis effective in treating the named disorder or condition.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient.

When introducing elements disclosed herein, the articles “a”, “an”,“the”, and “said” are intended to mean that there are one or more of theelements. The terms “comprising”, “having”, “including” are intended tobe open-ended and mean that there may be additional elements other thanthe listed elements.

In embodiments comprising an “additional” or “second” component orelement, such as an additional or second compound, the second componentas used herein is chemically different from the other components orfirst component. A “third” component is different from the other, first,and second components, and further enumerated or “additional” componentsare similarly different.

The term “and/or” as used herein means that the listed items arepresent, or used, individually or in combination. In effect, this termmeans that “at least one of” or “one or more” of the listed items isused or present. The term “and/or” with respect to pharmaceuticallyacceptable salts, solvates and/or radiolabeled versions thereof meansthat the compounds of the application exist as individual salts,hydrates or radiolabeled versions, as well as a combination of, forexample, a salt of a solvate of a compound of the application or a saltof a radiolabeled version of a compound of the application.

In understanding the scope of the present application, the term“comprising” (and any form of comprising, such as “comprise” and“comprises”), “having” (and any form of having, such as “have” and“has”), “including” (and any form of including, such as “include” and“includes”) or “containing” (and any form of containing, such as“contain” and “contains”), are inclusive or open-ended and do notexclude additional, unrecited elements, or process steps.

The term “consisting” and its derivatives as used herein are intended tobe closed terms that specify the presence of the stated features,elements, components, groups, integers, and/or steps, and also excludethe presence of other unstated features, elements, components, groups,integers and/or steps.

The term “consisting essentially of” as used herein is intended tospecify the presence of the stated features, elements, components,groups, integers, and/or steps as well as those that do not materiallyaffect the basic and novel characteristic(s) of features, elements,components, groups, integers, and/or steps.

The term “suitable” as used herein means that the selection of theparticular compound or conditions would depend on the specific syntheticmanipulation to be performed, the identity of the molecule(s) to betransformed and/or the specific use for the compound, but the selectionwould be well within the skill of a person trained in the art.

Terms of degree such as “substantially”, “about” and “approximately” asused herein mean a reasonable amount of deviation of the modified termsuch that the end result is not significantly changed. These terms ofdegree should be construed as including a deviation of at least ±5% ofthe modified term if this deviation would not negate the meaning of theword it modifies or unless the context suggests otherwise to a personskilled in the art.

The term “available”, as in “available hydrogen atoms” or “availableatoms” refers to atoms that would be known to a person skilled in theart to be capable of replacement by another atom or substituent.

II. Compounds and Compositions of the Application

One embodiment of the application includes a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, tautomer or optical isomer,or combination thereof:

wherein:R₁ is selected from the group consisting of C₁-C₆ lower alkyl, C₁-C₆lower alkoxy, C₁-C₆ lower alkyl-ester, C₁-C₆ lower alkyl-amide, C₁-C₆lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆-lower haloalkoxy,C₁-C₆-lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl,alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl,alkynyl, aryl-alkynyl, cycloalkenyl, heterocycloalkenyl,alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,and alkylene-O-alkylene-cycloalkyl,alkylene-O-alkylene-heterocycloalkyl, each R₁ group being optionallysubstituted with one or more independently-selected groups R₅;R₂ and R₃ are each independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; orR₂ and R₃ connect to form, together with the carbon atom to which theyare attached, a three to seven-membered carbocyclic or heterocyclicring; andR₄ is selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;X and Q are independently selected from CH₂, O, NR₇, S, SO and SO₂;R₅ is selected from the group consisting of hydroxy, halogen, cyano,nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂, C₁-C₆ lower alkyl,C₁-C₆ lower alkoxy, C₁-C₆ lower alkyl-ester, C₁-C₆ lower alkyl-amide,C₁-C₆ lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆ lower haloalkoxy,C₁-C₆ lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl,heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl,alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,alkylene-O-alkylene-cycloalkyl and alkylene-O-alkylene-heterocycloalkyl;andR₆ and R₇ are independently selected from the group consisting of H,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl,provided that at least one of R₁, R₂ and R₃ comprises a fluorine atom.

In some embodiments, the present application includes a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, tautomer oroptical isomer, or combination thereof:

wherein:R₁ is selected from the group consisting of C₁-C₆alkyl, C₁-C₆cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene-aryl,C₁-C₆alkylene-heteroaryl, C₂-C₆alkenyl, C₂-C₆alkenylenearyl,C₂-C₆alkenyleneheteroaryl, C₂-C₆alkynyl, C₂-C₆alkynylene-aryl,C₃-C₁₂cycloalkenyl, heterocycloalkenyl, C₁-C₆alkylene-O—C₁-C₆alkyl,C₁-C₆alkylene-O—C₃-C₁₂cycloalkyl, C₁-C₆alkylene-O-heterocycloalkyl,C₁-C₆alkylene-O—C₁-C₆alkylene-C₃-C₁₂cycloalkyl andC₁-C₆alkylene-O—C₁-C₆alkylene-heterocycloalkyl, each R₁ group beingoptionally substituted with one or more independently-selected groupsR₅;R₂ and R₃ are each independently selected from the group consisting ofhydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₃-C₁₂cycloalkyl, heterocycloalkyl, aryl and heteroaryl;orR₂ and R₃ connect to form, together with the carbon atom to which theyare attached, a three to seven-membered carbocyclic or heterocyclicring; andR₄ is selected from the group consisting of hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₃-C₁₂cycloalkyl,heterocycloalkyl, aryl and heteroaryl;X and Q are independently selected from CH₂, O, NR₇, S, SO and SO₂;R₅ is selected from the group consisting of hydroxy, halogen, cyano,nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkyl-ester, C₁-C₆alkyl-amide, C₁-C₆alkyl-acid,C₁-C₆haloalkyl, C₆haloalkoxy, C₁-C₆haloalkyl-ester, C₃-C₁₂cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆hydroxyalkyl,C₃-C₁₂hydroxycycloalkyl, hydroxy-heterocycloalkyl, C₁-C₆cyanoalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₂cycloalkenyl, heterocycloalkenyl,C₁-C₆alkylenearyl, C₁-C₆alkyleneheteroaryl, C₁-C₆alkylene-O—C₁-C₆alkyl,C₁-C₆alkylene-O—C₃-C₁₂cycloalkyl, C₁-C₆alkylene-O-heterocycloalkyl,C₁-C₆alkylene-O—C₁-C₆alkylene-C₃-C₁₂cycloalkyl andC₁-C₆alkylene-O—C₁-C₆alkylene-heterocycloalkyl; andR₆ and R₇ are independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl,C₃-C₁₂cycloalkyl, heterocycloalkyl, aryl and heteroaryl,provided that at least one of R₁, R₂ and R₃ comprises a fluorine atom.

In some embodiments, R₁ is selected from the group consisting ofC₁-C₆alkyl, C₁-C₆cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene-aryl, C₁-C₆alkylene-heteroaryl, C₃-C₁₂cycloalkenyl,heterocycloalkenyl, C₁-C₆alkylene-O—C₃-C₁₂cycloalkyl,C₁-C₆alkylene-O-heterocycloalkyl,C₁-C₆alkylene-O—C₁-C₆alkylene-C₃-C₁₂cycloalkyl andC₁-C₆alkylene-O—C₁-C₆alkylene-heterocycloalkyl, each R₁ group beingoptionally substituted with one or more independently-selected groupsR₅, wherein R₅ is selected from the group consisting of hydroxy,halogen, cyano, nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆, SO₂N(R₆)₂,C₁-C₆alkyl, C₁-C₆alkoxy, C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆hydroxyalkyl, C₁-C₆cyanoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl andC₁-C₆alkylene-O—C₁-C₆alkyl.

In some embodiments, R₁ is selected from the group consisting ofC₁-C₆cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene-aryl,C₆alkylene-heteroaryl, each R₁ group being optionally substituted withone or more independently-selected groups R₅, wherein R₅ is selectedfrom the group consisting of hydroxy, halogen, cyano, nitro, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl,C₁-C₆cyanoalkyl, and C₁-C₆alkylene-O—C₁-C₆alkyl.

In some embodiments, R₁ is selected from the group consisting of aryl,heteroaryl, C₁-C₆alkylene-aryl and C₁-C₆alkylene-heteroaryl, each R₁group being optionally substituted with one or threeindependently-selected groups R₅, wherein R₅ is selected from the groupconsisting of hydroxy, halogen, cyano, nitro, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₁-C₆cyanoalkyl, andC₁-C₆alkylene-O—C₁-C₆alkyl.

In some embodiments, R₁ is selected from the group consisting ofC₁-C₆alkylene-aryl and C₁-C₆alkylene-heteroaryl, each R₁ group beingoptionally substituted with one or three independently-selected groupsR₅, wherein R₅ is selected from the group consisting of hydroxy,halogen, cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, C₁-C₄hydroxyalkyl, C₁-C₄cyanoalkyl, andC₁-C₄alkylene-O—C₁-C₄alkyl.

In some embodiments, R₁ is selected from the group consisting ofC₁-C₄alkylene-aryl and C₁-C₄alkylene-heteroaryl, each R₁ group beingoptionally substituted with one or three independently-selected groupsR₅, wherein R₅ is selected from the group consisting of hydroxy, Cl, F,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄hydroxyalkyl, C₁-C₄cyanoalkyl, andC₁-C₄alkylene-O—C₁-C₄alkyl.

In some embodiments, R₁ is C₁-C₄alkylene-aryl optionally substitutedwith one R₅ group, wherein R₅ is selected from the group consisting ofCl, F, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkyl and C₁-C₄fluoroalkoxy.

In some embodiments, R₁ is C₁-C₂alkylene-phenyl substituted with one R₅group, wherein R₅ is selected from the group consisting of Cl, F, CH₃,CH₃O, CF₃, CF₂H, CF₃O and CHF₂O. In some embodiments, the R₅ group islocated at the para position.

In some embodiments, R₁ comprises a difluoromethoxy or atrifluoromethoxy substituent. In some embodiments, R₁ isp-trifluoromethoxybenzyl. In some embodiments, R₁ isp-difluoromethoxybenzyl. In some embodiments, at least one of R₂ and R₃is F and the other of R₂ and R₃ is H. In some embodiments, R₂ and R₃ areboth F. In some embodiments, R₁ is p-trifluoromethoxybenzyl orp-difluoromethoxybenzyl and at least one of R₂ and R₃ is F and the otherof R₂ and R₃ is H or R₂ and R₃ are both F.

In some embodiments, R₂ and R₃ are each independently selected from thegroup consisting of hydrogen, halogen, C₁-C₆alkyl and C₁-C₆haloalkyl. Insome embodiments, R₂ and R₃ are each independently selected from thegroup consisting of hydrogen, Cl, F, C₁-C₄alkyl and C₁-C₄haloalkyl. Insome embodiments, R₂ and R₃ are each independently selected from thegroup consisting of hydrogen, F, CH₃, CF₃ and CF₂H. In some embodiments,R₂ and R₃ are both H or are both F, or one of R₂ and R₃ is H and theother is F.

In some embodiments, R₄ is selected from the group consisting ofhydrogen C₁-C₄alkyl and C₁-C₄haloalkyl. In some embodiments, R₄ isselected from the group consisting of hydrogen, C₁-C₄alkyl andC₁-C₄haloalkyl. In some embodiments, R₄ is selected from the groupconsisting of hydrogen and CH₃. In some embodiments, R₄ is H.

In some embodiments, X and Q are independently selected from O and NR₇,wherein R₇ is selected from the group consisting of hydrogen, C₁-C₄alkyland C₁-C₄haloalkyl. In some embodiments, X and Q are independentlyselected from O and NR₇, wherein R₇ is selected from the groupconsisting of hydrogen and CH₃. In some embodiments, X is O. In someembodiments Q is selected from O and NR₇. In some embodiments Q is O.

In some embodiments, R₆ is selected from the group consisting ofhydrogen and C₁-C₄alkyl.

Representative compounds according to the current application include,but not limited to the following examples:

-   7-Benzyloxy-4H benzo[1,4]oxazin-3-one;-   7-(4-Fluoro-benzyloxy)-4H-benzo[1,4]oxazin-3-one;-   7-(4-Difluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one;-   7-(4-Trifluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one; and-   7-Benzyloxy-2,2-difluoro-4H-benzo[1,4]oxazin-3-one; or    a pharmaceutically-acceptable salt, solvate, tautomer, optical    isomer, or combination thereof.

In some embodiments, the present application includes a compound havingthe formula:

or a pharmaceutically-acceptable solvate or tautomer, or combinationthereof.

It will be understood by those of skill in the art that when compoundsof the present application contain one or more chiral centers, thecompounds of the application may exist in, and be isolated as,enantiomeric or diastereomeric forms, or as a racemic mixture. Thepresent application includes any possible enantiomers, diastereomers,racemates or mixtures thereof, of a compound of Formula (I). Theoptically active forms of the compound of the application may beprepared, for example, by chiral chromatographic separation of aracemate or chemical or enzymatic resolution methodology, by synthesisfrom optically active starting materials or by asymmetric synthesisbased on the procedures described hereinafter. Resolution of the finalproduct, an intermediate, or a starting material may be affected by anysuitable method known in the art. See, for example, Stereochemistry ofOrganic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994), incorporated by reference with regard tostereochemistry.

It will also be understood by those of skill in the art that certaincompounds of the present application may exist in solvated, for examplehydrated, as well as unsolvated forms. It will further be understoodthat the present application encompasses all such solvated forms of thecompounds of Formula (I).

Within the scope of the application are also salts of the compounds ofFormula (I). Generally, pharmaceutically acceptable salts of compoundsof the present application are obtained using standard procedures wellknown in the art, for example, by reacting a sufficiently basiccompound, for example an alkyl amine with a suitable acid, for example,HCl or acetic acid, to afford a salt with a physiologically acceptableanion. It is also possible to make a corresponding alkali metal (such assodium, potassium, or lithium) or an alkaline earth metal (such as acalcium) salt by treating a compound of the present application having asuitably acidic proton, such as a carboxylic acid or a phenol, with oneequivalent of an alkali metal or alkaline earth metal hydroxide oralkoxide (such as the ethoxide or methoxide), or a suitably basicorganic amine (such as choline or meglumine) in an aqueous medium,followed by conventional purification techniques. Additionally,quaternary ammonium salts can be prepared by the addition of alkylatingagents, for example, to neutral amines.

The compounds of Formulas (I) may crystallize in more than one form, acharacteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of Formula (I). Polymorphismgenerally can occur as a response to changes in temperature, pressure,or both. Polymorphism can also result from variations in thecrystallization process. Polymorphs can be distinguished by variousphysical characteristics known in the art such as x-ray diffractionpatterns, solubility, and melting point. Certain of the compoundsdescribed herein contain one or more chiral centers, or may otherwise becapable of existing as multiple stereoisomers. The scope of the presentapplication includes mixtures of stereoisomers as well as purifiedenantiomers or enantiomerically/diastereomerically enriched mixtures.Also included within the scope of the application are the individualisomers of the compounds represented by Formula (I), as well as anywholly or partially equilibrated mixtures thereof. The presentapplication also includes the individual isomers of the compoundsrepresented by the formulas above as mixtures with isomers thereof inwhich one or more chiral centers are inverted.

The compounds of the application may be used in their labelled orunlabelled form. In the context of this application the labelledcompound has one or more atoms replaced by an atom having an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. The labelling will allow easy quantitative detection ofsaid compound.

In another embodiment of the compounds of the present application may beuseful as diagnostic tools, radio tracers, or monitoring agents invarious diagnostic methods, and for in vivo receptor imaging. Thelabelled isomer of the application preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this application theradionuclide is preferably selected from ²H (deuterium), ³H (tritium),¹¹C, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F. The physical method fordetecting the labelled isomer of the present application may be selectedfrom Position Emission Tomography (PET), Single Photon Imaging ComputedTomography (SPECT), Magnetic Resonance Spectroscopy (MRS), MagneticResonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), orcombinations thereof.

In yet another one embodiment of the present application, the compoundof Formula (I) may be converted to a pharmaceutically acceptable salt orsolvate thereof, particularly, an acid addition salt such as ahydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,tartrate, citrate, methanesulphonate or p-toluenesulphonate.

In yet another aspect, there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one pharmaceuticallyacceptable carrier and/or excipient. In a further aspect, the carrier isa pharmaceutically-acceptable carrier.

In another aspect, there is provided a pharmaceutical compositioncomprising therapeutically effective amount of a compound of Formula (I)to treat medical conditions such as epilepsy, neuropathic pain, acuteand chronic inflammatory pain, migraine, tardive dyskinesia, anxiety andother related CNS disorders; such compositions can comprise a compoundof Formula (I) in association with one or more pharmaceuticallyacceptable diluents, excipients and/or inert carriers.

For pharmaceutical use, the compounds of the present application are,for instance, administered orally, sublingually, rectally, nasally,vaginally, topically (including the use of a patch or other transdermaldelivery device), by pulmonary route by use of an aerosol, orparenterally, including, for example, intramuscularly, subcutaneously,intraperitoneally, intra-arterially, intravenously or intrathecally.Administration can be by means of a pump for periodic or continuousdelivery. The compounds of the application are administered alone, orare combined with a pharmaceutically-acceptable carrier or excipientaccording to standard pharmaceutical practice. For the oral mode ofadministration, the compounds of the application are used in the form oftablets, capsules, lozenges, chewing gum, troches, powders, syrups,elixirs, aqueous solutions and suspensions, and the like. In the case oftablets, carriers that are used include lactose, sodium citrate andsalts of phosphoric acid. Various disintegrants such as starch, andlubricating agents such as magnesium stearate and talc, are commonlyused in tablets. For oral administration in capsule form, usefuldiluents are lactose and high molecular weight polyethylene glycols. Ifdesired, certain sweetening and/or flavoring agents are added. Forparenteral administration, sterile solutions of the compounds of theapplication are usually prepared, and the pHs of the solutions aresuitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled to render the preparationisotonic. For ocular administration, ointments or droppable liquids maybe delivered by ocular delivery systems known to the art such asapplicators or eye droppers. Such compositions can include mucomimeticssuch as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as ascorbicacid, EDTA or benzylchromium chloride, and the usual quantities ofdiluents and/or carriers. For pulmonary administration, diluents and/orcarriers will be selected to be appropriate to allow the formation of anaerosol.

Suppository forms of the compounds of the application are useful forvaginal, urethral and rectal administrations. Such suppositories willgenerally be constructed of a mixture of substances that is solid atroom temperature but melts at body temperature. The substances commonlyused to create such vehicles include theobroma oil, glycerinatedgelatin, hydrogenated vegetable oils, and mixtures of polyethyleneglycols of various molecular weight and fatty acid esters ofpolyethylene glycol. For example, see Remington's PharmaceuticalSciences, 16th Ed. (Mack Publishing, Easton, Pa., 1980, pp. 1530-1533)for further discussion of suppository dosage forms. Analogous gels orcreams can be used for vaginal, urethral and rectal administrations.

Numerous administration vehicles will be apparent to those of ordinaryskill in the art, including without limitation slow releaseformulations, liposomal formulations and polymeric matrices.

Examples of pharmaceutically acceptable acid addition salts for use inthe present application include those derived from mineral acids, suchas hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids, and organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,p-toluenesulphonic and arylsulphonic acids, for example. Examples ofpharmaceutically acceptable base addition salts for use in the presentapplication include those derived from non-toxic metals such as sodiumor potassium, ammonium salts and organoamino salts such as triethylaminesalts. Numerous appropriate such salts will be known to those ofordinary skill.

III. Methods of Use of the Application

In yet another aspect there is provided a method for treating at leastone of epilepsy, neuropathic pain, acute and chronic inflammatory pain,migraine, tardive dyskinesia, anxiety and other related CNS disorders ina mammal, comprising administering to the mammal a therapeuticallyeffective amount of a compound or composition noted above. In a furtheraspect, the mammal is a human. In still a further aspect, the compoundor composition is administered orally and/or parenterally. In yetanother aspect, the compound or composition is administeredintravenously and/or intraperitoneally.

In yet a further aspect, there is provided the use of the compound orcomposition noted above for manufacture of a medicament for treatment ofat least one of epilepsy, neuropathic pain, acute and chronicinflammatory pain, migraine, tardive dyskinesia, anxiety and otherrelated CNS disorders. In yet a further aspect, there is provided theuse of the compound or composition noted above for treatment of at leastone of epilepsy, neuropathic pain, acute and chronic inflammatory pain,migraine, tardive dyskinesia, anxiety and other related CNS disorders ina mammal. In a further aspect, the mammal is a human. In still a furtheraspect, the compound or composition is administrable orally and/orparenterally. In yet another aspect, the compound or composition isadministrable intravenously and/or intraperitoneally.

In some embodiments, the CNS diseases, conditions or disorders, include,but not limited to, epilepsy, epileptogenesis, convulsions, seizuredisorders, tremor, essential tremor, myoclonus, anxiety, Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles dela Tourette's syndrome, depression, mania, manic depression, psychosis,schizophrenia, obsessive compulsive disorders (OCD), panic disorders, aneating disorder including anorexia nervosa, bulimia and obesity,narcolepsy, nociception, AIDS-dementia, senile dementia, peripheralneuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia,post-traumatic syndrome, social phobia, a sleeping disorder, pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, mutism, trichotillomania, jet-lag,hypertension, cardiac arrhythmias, a smooth muscle contraction disorderincluding convulsive disorders, angina pectoris, premature labor,convulsions, diarrhea, asthma, premature ejaculation and erectiledifficulty, an endocrine system disorder including thyrotoxicosis andpheochromocytoma, a neurodegenerative disorder, including transientanoxia and induced neuro-degeneration, pain, mild, moderate or severepain, acute pain, chronic pain, pain of recurrent character, neuropathicpain, pain caused by migraine, postoperative pain, phantom limb pain,neuropathic pain, chronic headache, central pain, pain related todiabetic neuropathy, to post-therpetic neuralgia or to peripheral nerveinjury and an inflammatory disorder.

In a further aspect, the compounds of the present application may beuseful as diagnostic tools or monitoring agents in various diagnosticmethods, and in particular for in vivo receptor imaging (neuroimaging),and they may be used in labelled or unlabelled form. In some embodimentsthe disease, disorder or condition contemplated according to theapplication is selected from epilepsy, epileptogenesis, convulsions,seizure disorders, tremor, essential tremor, myoclonus, anxiety,Parkinson's disease, tardive dyskinesia and hyperkinesia. In someembodiments, the disease, disorder or condition is epilepsy,epileptogenesis, convulsions or seizure disorders.

In some further embodiments, the disease, disorder or condition is pain,including mild, moderate or even severe pain of acute, chronic orrecurrent character, as well as pain caused by migraine, postoperativepain, or phantom limb pain. The pain may in particular be neuropathicpain, chronic headache, central pain, pain related to diabeticneuropathy, to post-herpetic neuralgia, or to peripheral nerve injury.Finally the compounds of the application may be useful for the treatmentof withdrawal symptoms caused by termination of use of addictivesubstances. Such addictive substances include nicotine containingproducts such as tobacco, opioids such as heroin, cocaine or morphine,benzodiazepines and benzodiazepine-like drugs, and alcohol. Withdrawalfrom addictive substances is in general a traumatic experiencecharacterized by anxiety and frustration, anger, anxiety, difficultiesin concentrating, restlessness, decreased heart rate and/or increasedappetite and/or weight gain.

The physician or other health care professional can select theappropriate dose and treatment regimen based on, for example, thesubject's weight, age, and physical condition. Dosages will generally beselected to maintain a serum level of compounds of the applicationbetween about 0.01 μg/cc and about 1000 μg/cc, or between about 0.1μg/cc and about 100 μg/cc. For parenteral administration, an alternativemeasure of dosage amount is from about 0.001 mg/kg to about 10 mg/kg(alternatively, from about 0.01 mg/kg to about 10 mg/kg), or from about0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg). Fororal administrations, an alternative measure of the administrationamount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kgto about 10 mg/kg), or from about 0.01 mg/kg to about 1 mg/kg (fromabout 0.1 mg/kg to about 1 mg/kg). For administrations in suppositoryform, an alternative measure of the administration amount is from about0.1 mg/kg to about 10 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg.

IV. Methods of Preparation of the Compounds of the Application

The application additionally provides a process for the preparation ofcompounds of Formula (I). General and specific processes are discussedin more detail set forth in the Examples below.

The compounds of this application may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theapplication are prepared in the working Examples.

In all of the schemes described below, protecting groups for sensitiveor reactive groups are employed where necessary in accordance withgeneral principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of Formula (I).

Compounds of the present application can be prepared by varioussynthetic processes. The selection of a particular process to prepare agiven compound of Formula (I) is within the purview of the person ofskill in the art. The choice of particular structural features and/orsubstituents may therefore influence the selection of one process overanother.

Some starting materials for preparing compounds of the presentapplication are available from commercial chemical sources. Otherstarting compounds, as described below, are readily prepared fromavailable precursors using straightforward transformations that are wellknown in the art.

Within these general guidelines, the compounds of Formula (I) generallycan be prepared according to the methods illustrated in Schemes I toIII. Variables in these methods are as defined for Formula (I) hereinabove unless otherwise specified.

The compounds of this application wherein R₁, R₂ and R₃ are as definedabove and Q is O or NR₇ wherein R₇ is as defined above can be prepared,for example, according to Scheme I. The benzoxazine-based intermediate(C) can be synthesized in a straightforward process from thecommercially available 2-amino-5-nitro-phenol (A) by a condensationreaction of a halo-acetyl chloride, a non-limiting example ischloro-acetyl chloride (B) in the presence of a base, a non-limitingexample of which is potassium or cesium carbonate in a polar solvent,non-limiting examples are acetonitrile and dimethyl-formamide to affordthe corresponding to the 7-nitro-4H-benzo[1,4]oxazin-3-one intermediates(C), hydrogenation, non-limiting examples of which are catalytichydrogenation and iron powder, of the nitro group yields7-amino-4H-benzo[1,4]oxazin-3-one derivatives (D). Subsequentreductive-amination reaction with an appropriate aldehydes leads to thesecondary amine intermediates (E), that are subsequently reacted with anhalide, a non-limiting examples of which are substituted benzyl-chlorideor bromide in the presence of a base, a non-limiting example of which ispotassium or cesium carbonate in a polar solvent, non-limiting examplesare acetonitrile, dimethyl-formamide and ethanol, to provide thetargeted compounds (F). On the other hand, the amino functionality of7-amino-4H-benzo[1,4]oxazin-3-one (D) is transformed to the keyintermediate 7-hydroxy-4H-benzo[1,4]oxazin-3-onehydoxy intermediates (G)using sodium nitrite in the presence of acid, a non-limiting example ofwhich is sulfuric acid. Subsequent alkylation with R₁-LG (LG is aleaving group, a non-limiting examples of which is bromo, iodo orchloro) leads to the final compounds (I) (Pico Z T. et al., Eur. J. Med.Chem., 2008, 43, 1216-1221).

Alternatively, the compounds of the application wherein R₁, R₂ and R₃are as defined above and X is C, O, S or NR₇ wherein R₇ is as definedabove can be prepared according to Scheme II. Regio-selectivehalogenations of benzo[1,4]oxazin-3-one derivatives (J) with halogen,non-limiting examples of which are bromine, iodine and chlorine inacidic reaction conditions, a non-limiting example of which is glacialacetic acid in the presence of a non-polar solvent, a non-limitingexample of which is chloroform provides the7-halo-4H-1,4-benzoxazin-3-one intermediates (K) (Hanson J R et al., J.Chem. Research, 2003, 1120-1128) that were used for the couplingreactions to form compounds with X is an oxygen (I), (Boyan X. et al.,Chem. Let., 2008, 37(2), 202-203; Nam T. et al., Synthesis, 2005, 9,1397-1404; Hyun K. et al., Org. Let., 2011, 13(9), 2368-2371, Rajesh P.,Synthesis, 2010, (24), 4268-4272; Chuan T., Chinese Chem. Lett. 2009,20(10), 1170-1174), compounds with X is a carbon (I) (Martinez, G. etal. J. Med. Chem., 1992, 35(4), 620-628; Lemhadri M. et al., Synthesis,2009, 6, 1021-1035; Alacid E, et al., Eur. J. Org. Chem. 2008, 18,3102-3106; Bing M. et al., Tetrahedron 2007, 63(46), 11475-11488),compounds with X is a nitrogen (N) (Xiaolin L. et al., 2010, FamingZhuanli Shenqing, 101863860; Qilong S. et al., 2008, J. Am. Chem. Soc.,130(20), 6586-6596; Jadhav, V H. et al., Cat. Comm., 2006, 8(1), 65-68),and compounds with X is a sulfur (I) (Chad E C. et al., J. Org. Chem.,74(10), 4005-4008; 2009; Keniley L. et al., Inorg. Chem. 2010(Washington, D.C., United States), 49(4), 1307-1309; Sakaki S. et al.,Bioorg. Med. Chem. Lett., 2007, 17(17), 4804-4807).

Alternatively, the compounds of this application wherein R₁, R₂ and R₃are as defined above and Q is oxygen may be prepared according to SchemeIII. Mono-protection of commercially available resorcinol (O), anon-limiting example of which is benzylation to provide3-benzyloxyphenol (P), which is subjected to nitration conditions toyield (Q), and subsequent nitro group reduction leads to the2-amino-5-benzyloxy-phenol intermediate (R) (Ming X. et al., ChineseChem. Lett., 2007, 18(8), 905-908; Maleski, R J. et al. Synth. Commun.,1995, 25(15), 2327-35). Intermediate (R) is transformed to (I) in asimilar manner as described in Scheme I.

The above disclosure generally describes the present application. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the application.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXAMPLES Abbreviations

atm Atmosphere

aq. Aqueous

BI NAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Boc tert-butoxycarbonyl

DCM Dichloromethane

DEA N,N-Diisopropyl ethylamine

DIBAL-H Diisobutylaluminium hydride

DIC N,N′-Diisopropylcarbodiimide

DMAP N,N-Dimethyl-4-aminopyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

DPPF Diphenylphosphinoferrocene

Et₂O Diethylether

EtOAc Ethyl acetate

EtOH Ethanol

Etl Iodoethane

Et Ethyl

Fmoc 9-fluorenylmethyloxycarbonyl

hr(s) hour(s)

mins minutes

HetAr Heteroaryl

HPLC High performance liquid chromatography

LAH Lithium aluminium hydride

LCMS HPLC mass spec

MCPBA m-Chlorbenzoic acid

MeCN Acetonitrile

MeOH Methanol

Min Minutes

MeI Iodomethane

Me Methyl

n-BuLi 1-Butyllithium

NaOAc Sodium acetate

NaOH Sodium hydroxide

NaH Sodium hydrade

NMR Nuclear magnetic resonance

NMP N-Methyl pyrrolidinone

NMM N-Methyl morpholine

ON Over Night

RT Room Temperature

TEA Triethylamine

THF Tetrahydrofurane

OMs Mesylate or methane sulfonate ester

OTs Tosylate, toluene sulfonate or 4-methylbenzene sulfonate ester

PCC Pyridinium chlorochromate

PPTS Pyridinium p-toluenesulfonate

TBAF Tetrabutylammonium fluoride

pTsOH p-Toluenesulfonic acid

SPE Solid phase extraction (usually containing silica gel formini-chromatography)

sat. Saturated

Gp Protecting group

LG Leaving group

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions conducted under an inert atmosphereat room temperature unless otherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument. Chemical shifts are expressed in parts permillion (ppm, δ units). Coupling constants are in units of hertz (Hz).Splitting patterns describe apparent multiplicities and are designatedas s (singlet), d (doublet), t (triplet), q (quartet), m (multiple), orb (broad).

Example 1: Representative Synthesis of Exemplary Compounds of theApplication

Exemplary compounds I(A) to I(E) of the present application are asillustrated in the following Table 1, their pharmaceutically acceptablesalts, hydrates, solvates, optical isomers, and combinations thereof:

TABLE 1 Compound # Chemical Structure Nomenclature 1 (Comparativeexample)

7-Benzyloxy-4H benzo[1,4]oxazin-3-one I(A)

7-(4-Fluoro-benzyloxy)-4H- benzo[1,4]oxazin-3-one I(B)

(7-(4-Difluoromethoxy- benzyloxy)-4H- benzo[1,4]oxazin-3-one I(C)

7-(4-Trifluoromethoxy- benzyloxy)-4H- benzo[1,4]oxazin-3-one I(D)

7-Benzyloxy-2,2-difluoro- 4H-benzo[1,4]oxazin-3-one

Preparation of 7-Benzyloxy-4H benzo[1,4]oxazin-3-one (Compound1)—Comparative Example

Step. 1: 7-Hydroxy-4H-benzo[1,4]oxazin-3-one (B)

Method (1):

K₂CO₃ (30.6 g, 221.4 mmol, 4 eq) was dissolved in water (120 mL) in a250 mL round bottomed flask, vacuum degassed 3 times, then cooled to 0°to 5° C. 4-Amino resorcinol HCl (A) (9 g, 55.69 mmol, 1 eq) was addedthrough a strong nitrogen purge, and the blue solution was againdegassed 3 times. Choro-acetyl chloride (5.4 mL, 69.61 mmol, 1.25 eq)was dissolved in toluene (27 mL), and was added over 30 min maintainingthe temperature below 5° C. The ice bath was removed, and the mixture(biphasic with suspended crystalline product) was stirred overnight.7-Hydroxy-4H-benzo[1,4]oxazin-3-one (B) was then isolated via filtrationgiving 7.6 g, 83.5%) after a water wash (2×200 mL) and drying; HRMS[M+H] calcd, 166.04987; found, 166.04929.

Method (2):

To a solution of 4-aminoresorcinol hydrochloride (A) (5.0 g, 30.94 mmol)in acetonitrile (100 mL) at 0° C. was added cesium carbonate (30.2 g,92.80 mmol) followed by a dropwise addition of chloroacetyl chloride(2.6 mL, 32.49 mmol). The reaction mixture was stirred at roomtemperature for overnight and then was diluted with absolute ethanol(100 mL). The insoluble materials were filtered and rinsed with 2× 50 mLof absolute ethanol. The filtrate was concentrated under vacuum toafford the crude product as a purple oily solid. The solid was dissolvedin methanol (50 mL), silica was added, and the solvent was removed againunder vacuum. The solid was loaded onto a pad of silica (800 mL) andeluted with 1:1 ethyl acetate in dichloromethane followed by 100%dichloromethane. After removal of the solvents, the product (B) wasobtained as an orange solid (3 g, 60%).

Step. 2: 7-benzyloxy-4H-1,4-benzoxazin-3-one (Compound 1)

A mixture of the above 7-Hydroxy-4H-benzo[1,4]oxazin-3-one (B, 2.5 g15.43 mmol) and bromomethyl-benzene (3.3 g 17.74 mmol) in 65 mlanhydrous ethanol was refluxed for 4 to 6 hours in the presence of K₂CO₃(12.8 g, 92.6 mmol). After the solvent was removed, the residue wasdiluted with water (50 mL). The precipitate was filtered. The solidobtained was dissolved in EtOAc (50 mL), and washed with water and brine(2×50 mL). Dried over MgSO₄, concentrated led to the crude product, thiswas triturated with ether and filtered to get pure product (2 g). Thisprocess was repeated 3×) to provide a total of (3.2 g, 82%) of compound1 as white light powder. ¹H-NMR (300 MHz, CDCl₃): δ 8.16 (broad s, 1H),7.40-7.31 (m, 5H) (s, 1H), 6.71 (s, 1H), 6.69-6.57 (m, 2H), 5.01 (s,2H), 4.58 (s, 2H).

In a similar procedure the following compounds were synthesized asillustrated in the following Table 2:

TABLE 2 Compound # Structure Name Yield I(A)

7-(4-Fluoro- benzyloxy)-4H- benzo[1,4]oxazin- 3-one 0.99 g, (87%) NMR¹H-NMR (300 MHz, CDCl₃): δ 8.18 (broad s, 1H), 7.39-7.36 (m, 2H),7.09-7.07 (m, 2H), 6.65 (dd, 1H), 6.56 (m, 2H), 4.97 (s, 2H), 4.59 (s,2H). I(B)

(7-(4- Difluoromethoxy- benzyloxy)-4H benzo[1,4]oxazin- 3-one 2.18 g,(72%) NMR ¹H-NMR (300 MHz, CDCl₃): δ 7.91 (broad s, 1H), 7.40 (d, 2H),7.13 (d, 2H), 6.71-6.55 (m, 4H), 4.98 (s, 2H), 4.59 (s, 2H). I(C)

7-(4- Trifluoromethoxy- benzyloxy)-4H- benzo[1,4]oxazin- 3-one  1.5 g,(83%) NMR ¹H-NMR (300 MHz, CDCl₃): δ 8.16 (broad s, 1H), 7.64 (d, 2H),7.55 (d, 2H), 6.73-6.70 (m, 1H), 6.63-5.55 (m, 2H), 5.07 (s, 2H), 4.59(s, 2H). I(D)

7-Benzyloxy-2,2- difluoro-4H- benzo[1,4]oxazin- 3-one 0.84 g, (50%) NMR¹H NMR (300 MHz, CDCl₃): δ (ppm) 8.19 (broad, 1H), 7.41- 7.32 (m, 5H),6.88-6.76 (3, mH), 5.04 (s, 2H).

Example 2: The Maximal Electroshock Seizure (MES) Rat Model (EpilepsyIndication) Animals and Housing:

Male, Sprague-Dawley rats and CD-1 mice were used for all studies. Allanimals were allowed ad-lib access to food and water except duringexperiment. Animals were housed within an animal vivarium maintainedunder a 12 h light:dark cycle (lights on: 07:00 h), and all experimentswere conducted in the animals light phase. For all experiments, animalswere habituated to the vivarium for a minimum of 72 h beforeexperimentation. The experimental procedures used in the presentinvestigation were conducted under the Association for Assessment andAccreditation of Laboratory Animal Care (AAALAC) and the CanadianCouncil on Animal Care (CCAC) guidelines.

All compounds were sonicated in 5% Tween 80® in saline ormethylcellulose 0.5% (wgt/vol), using MC and sterile water and injectedin a dose volume of 5 ml/kg or 10 ml/kg (rat), and 10 ml/kg (mouse).Drugs were administered by either the oral, intraperitoneal orintravenous route.

Male Sprague-Dawley rats of body weight 80-100 g were used for thesestudies. Each experiment was conducted over 3 consecutive days. On day 1and 2, each rat received a single electrical stimulus (150 mA, 0.2 sduration, 60 Hz) via corneal electrodes moistened with saline (Shockstimulator type 221: Harvard apparatus). Only rats that displayed a fulltonic extensor on day 1 and 2 were entered into the drug study conductedon day 3. Typically this reflected approximately 70-90% of the initialgroup. In this way, rats which did not produce a reliable tonic extensorto the MES stimulus were excluded from the experiment.

On the test day following a defined drug pretreatment period, ratsreceived a maximal electroshock (150 mA, 0.2 s duration, 60 Hz) viacorneal electrodes. Protection was defined as absence of a full tonicseizure within 10 s of stimulus delivery. Twenty minutes before the MESprocedure, the animals were tested on a fixed speed rotorod (best scorefrom 3 trials at 8 r.p.m, trial duration=60 s) to give an earlyassessment of drug effect on gross motor function.

Several exemplary compounds of the application were active in thisassay, with ED₅₀ values of below 50 mg/kg in rat (po) as illustrated inthe following Table 3:

TABLE 3 MES (po) ED₅₀ Rotorod (po) ED₅₀ Compound # mg/kg, [4 hours]mg/kg, [4 hours] PI I(B) 20.1 ± 0.7 >500 >25 I(D) 30.5 ± 0.8 >120 >3.91 >300 — —

Example 3: s.c Pentylenetetrazole (PTZ) Mouse Model (EpilepsyIndication)

Sixty minutes following drug or vehicle pretreatment, all mice receiveda single subcutaneous injection of pentylenetetrazol (PTZ; 85 mg/kg).The animals were then transferred to single observation cages(dimension: 11.5″×7.5″×5″) and observed continuously for 30 min.Preliminary experiments established that at the 85 mg/kg s.c dose ofPTZ, at least one single episode of clonic seizure was elicited in >95%of control animals. Protection was defined as complete absence of aclonic seizure over the 30 min observation period. In the event of aseizure, the onset latency from PTZ injection was recorded.

Several exemplary compounds of the application demonstratedanticonvulsant activity in this assay, with ED₅₀ values of below 300mg/kg in mice (ip). Comparative compound 1 had ED₅₀ values of above 300mg/kg in mice (ip).

Example 4: 6-Hz Psychomotor Seizure Mouse Model (Epilepsy Indication)

Sixty minutes following drug or vehicle pretreatment, all mice receivedan electrical stimulus (6 Hz, 0.2 ms pulse width, 3 s duration, 32 mA)via corneal electrodes moistened with saline (ECT unit 57800; UgoBasile). Preliminary experiments established that these stimulusparameters elicited a psychomotor seizure, defined as the expression ofat least one of the following behaviors: stun/immobility, forelimbclonus, straub tail, vibrissae tremor, lateral head movement in >95% ofcontrol animals. Protection was defined as complete absence of all theabove behaviors within 20 s of stimulus delivery. The effective dose ofcompound necessary to protect against psychomotor seizures to 50% ofcontrols (i.e. ED₅₀) was determined by curve fitting program (Prismv.4.02).

Compound I(B) of the application demonstrated anticonvulsant activity inthis assay, with ED₅₀ values of below 100 mg/kg in mice (ip) asillustrated in the following Table 4:

TABLE 4 6 Hz (ip) ED₅₀ Rotorod (ip) ED₅₀ Compound # mg/kg, [0.5 hour]mg/kg, [0.5 hours] PI I(B) 17.4 ± 0.6 >500 >28

Example 4: Intravenous Metrazol Seizure Threshold Test (i.v. MET)

The iv-Met test provides a measure of a test substance's ability toraise or lower seizure threshold. Two doses of the test compound areusually employed in this test, the MES ED₅₀ and the TD₅₀ determinedfollowing ip quantification testing in mice. Randomly selected mice areinjected intraperitoneally 2 minutes apart with either the vehicle orthe two test drug doses, maintaining the same order of dosing until 30mice have been injected. At the previously determined TPE, 0.5%heparinized Metrazol solution is infused at a constant rate of 0.34ml/min into a lateral tail vein of an unrestrained mouse. Infusion is bymeans of a Sage syringe pump (model 341 A) and a 10 ml B-D plasticsyringe connected to a length of No 20 P.E. tubing. A 27 gauge stainlesssteel needle with the hub removed is connected to the tubing andinserted into a vein, bevel side up and secured to the tail by a narrowpiece of adhesive tape. For the placement of the needle, the mouse isrestrained in a cone shaped device with only the tail exposed. The rateselector is set on 4, and the switch is set at ml/min. At the start ofthe infusion, a hemostat clamped to the tubing to prevent backflow isremoved, the infusion started, and two stopwatches started. The time inseconds from the start of the infusion to the appearance of the “firsttwitch” and the onset of sustained clonus is recorded. The times to eachendpoint are converted to mg/kg of Metrazol for each mouse as follows:

$\begin{matrix}{{{mg}\text{/}{kg}\mspace{14mu} {Met}} = \frac{\begin{matrix}{{Inf}\mspace{14mu} {time}\mspace{14mu} (T) \times {Rate}\mspace{14mu} {of}\mspace{14mu} \inf \mspace{14mu} \left( {{mL}\text{/}\min} \right) \times} \\{{mg}\mspace{14mu} {Met}\text{/}{mL} \times 1000\mspace{14mu} g}\end{matrix}}{60\mspace{14mu} \sec \times {Weight}\mspace{14mu} (W)\mspace{14mu} {of}\mspace{14mu} {animal}\mspace{14mu} {in}\mspace{14mu} g}} \\{= {\frac{T \times 0.34 \times 5 \times 1000}{60 \times W} = {\frac{28.33 \times T}{W} = {{mg}\text{/}{kg}\mspace{14mu} {of}\mspace{14mu} {Metrazol}}}}}\end{matrix}$

The mean and standard error for each of the 3 groups and thesignificance of the difference between the test groups and the controlare calculated. An increase in mg/kg to first twitch or to clonusindicates the test substance increases seizure threshold, whereas adecrease indicates that the test substance decreases seizure thresholdand may be pro-convulsant.

Exemplary compounds of the application were found to increases seizurethreshold in this model. For example, compound I(B) dose-dependentlyincreased the seizure threshold in this mouse Seizure model (FIG. 1).

Example 5: Frings Audiogenic Seizure (AGS)-Susceptible Mouse Model

Frings audiogenic seizure (AGS)-susceptible mice model examines theability of an investigational drug to alter the onset and/or severity ofseizures in a genetic mouse model of seizure susceptibility. Mice aregenetically susceptible to sound-induced reflex seizures. Their seizurephenotype is characterized by wild running, loss of righting reflex,tonic flexion, and tonic extension in response to high-intensity soundstimulation. In contrast to other seizure models, the FringsAGS-susceptible mouse, like the DBA2J AGS-susceptible mouse, isnon-discriminatory with respect to clinical categories of anticonvulsantdrugs, and thus, does not offer high predictive value in screeninginvestigational compounds. For example, the prototypical anticonvulsantsphenytoin and ethosuximide display widely divergent clinical spectrumsin humans, but are both active against sound-induced seizures in mice.Yet, the preclinical utility of this animal model rests in the usefulinformation that can be obtained within a genetically susceptible modelof seizures. Further, efficacy in this model provides proof of conceptof brain bioavailability following systemic administration. The FringsAGS-susceptible mouse has a well-validated epilepsy phenotype that makesit particularly useful as a screening model. Beginning at about 21 daysof age, Frings AGS-susceptible mice display prominent seizure activityin response to a high-intensity sound stimulus. They then remainsusceptible to sound throughout their life. This is in stark contrast tothe DBA2J AGS-susceptible mouse, which is the other common model ofsound-induced seizures, as DBA2J mice are only susceptible tosound-induced seizures during a narrow developmental window (post-nataldays 18-30). Thus, the Frings AGS-susceptible mouse seizures respond toa wide range of CNS-active drugs and display sound-induced seizuresthroughout their lifetime. In this regard, Frings AGS-susceptible miceare a highly useful screening model for the identification andcharacterization of compounds potentially effective against inheritedepilepsy.

Methods:

Male and female Frings audiogenic seizure-susceptible mice (18-25 g) aremaintained in an in-house colony at the University of Utah. For eachscreening test, groups of 8 mice each are treated i.p. with varyingdoses of the investigational compound. At the time of peak effect asdetermined in the MES test (Test 4 in CF1 mice), individual mice areplaced in a round plexiglass jar (diameter, 15 cm, height, 18 cm) andexposed to a sound stimulus of 110 decibels (11 KHz) delivered for 20sec. Mice are observed for 25 sec for the presence or absence of hindlimb tonic extension. Mice not displaying hind limb tonic extension areconsidered protected. The severity of a seizure may also be quantitatedby assigning a numerical score to the observed response, e.g. noresponse—0; wild running for <10 sec—1; wild running for >10 sec—2;clonic seizure—3; forelimb extension/hind limb flexion—4; tonicseizure—5.

Exemplary compounds of the application are effective in this mousemodel. For example. compound I(B) dose-dependently blocks AGS in theFrings AGS-susceptible mouse model with an ED50 of 13.00±2.00 mg/kg andsuperior Protective index compared to antiepileptic drugs (TD₅₀/ED₅₀) of77, see following Table 5):

TABLE 5 ED₅₀ P.I^(a) Drug (mg/kg, i.p.) (TD₅₀/ED₅₀)^(b) Compound I(B)13.0 ± 2.0 77 Carbamazepine 11.2 4.1 Ethosuximide 328 1 Felbamate 10 22Gabapentin 91.1 >5.5 Lamotrigine 2.39 13 Levetiracetam NT NT Phenytoin3.8 11 Valproic Acid 155 2.6 ^(a)Protective index = TD₅₀/ED₅₀)^(b)Calculated with TD₅₀ in mice and ED₅₀ in Frings mice NT: Not tested

Example 6: Hippocampal Kindled Rat Model (Focal Seizures)

Hippocampal Kindled Rat Test is designed to quantify the anti-convulsanteffects of a test compound in the kindled rat model. Rats treated byi.p. injection.

The Kindled Rat is a model of temporal lobe epilepsy, which is the mostcommon and drug-resistant type of adult focal epilepsy (Morimoto et al.,2004). In this model, repetitive electrical stimulation of thehippocampus causes progressively stronger seizure responses triggered bystimuli that initially did not elicit such responses. This acquiredhyper-responsiveness is called kindling and results not only inincreased seizure responses but also in an elongation of theafter-discharge duration seen on an EEC recording. Electrodes areimplanted into the hippocampus of anesthetized rats, which are thenallowed to recover for one week. Following the rapid kindling protocol(Lothman and Williamson, Brain Res 1994, 649:71-84), the rats arestimulated with 200 jiA for 10 s, 50 Hz, every 30 minutes for six hourson alternate days until they are fully kindled (4-5 stimulus days).After one week of rest, the animals are given the same electricalstimulus which serves as a baseline. The animals are pretreated with thetest compound (generally via i.p. injection) and then tested at variousintervals. At each time point, the behavioral seizure score (BSS) andafter-discharge duration (ADD) is recorded. The BSS's are scoredaccording to the following criteria (Racine, Electroencephalogr ClinNeurophysiol 1972, 32:281-94): Stage 1—mouth and facial clonus; Stage2—stage 1 plus head nodding; Stage 3—stage 2 plus forelimb clonus; Stage4—stage 3 plus rearing; and Stage 5—stage 4 plus repeated rearing andfalling.

The afterdischarge threshold (ADT) can also be measured in the kindledrat. The ADT is defined as the lowest current at which an afterdischargeof at least 4 s is elicited. On the day of the test the individual ADTof each rat is determined by increasing the current intensity in astepwise fashion until the rat displays an electrographic afterdischargewith duration of at least 4 sec. The initial stimulation is conducted atan intensity of 20 uA with 10 uA increments every 1-2 min until anafterdischarge is elicited. Fifteen minutes after the pre-drug thresholddetermination, a single dose of the test substance is administered totwo animals in a volume of 0.04 ml/10 g body weight. In this way theanimals serves as its own control. The individual rat ADT is thendetermined at varying times (i.e., 0.25, 1, 2, and 4 hr) after drugadministration.

Exemplary compounds of the application were effective in this model. Forexample, compound I(B) (<300 mg/kg i.p.) produced a dose relatedsuppression of fully kindled (stage 5) seizures compared to vehiclecontrols.

Example 7: Amygdala Kindled Rat Model (Focal Seizures)

Amygdala kindling model is an animal model for complex partial seizures,which is the most common type of epilepsy in adults and is often drugresistant. Exemplary compounds of the application were effective in thismodel. For example, compound I(B) (<100 mg/kg i.p.) produced a doserelated suppression of fully kindled (stage 5) seizures compared tovehicle controls.

Example 8: Corneal Kindling Mouse Model (Focal Seizures)

Mice are kindled electrically with 3 sec stimulation, 8 mA, 60 Hz, andconeal electrodes to a criterion of 10 consecutive Stage 5 seizures(facial clonus and head nodding progressing to forelimb clonus, andfinally rearing and falling accompanied by a generalized clonic seizureas described by Racine (Racine R J. Neurophysiol., 1972. 32: p. 281-294)Stage 5 is generally reached after twice daily stimulation for 8 days.With continued stimulation once a day, animals usually progress to areproducible Stage 5 after 10-14 additional days. At least 72 hoursafter the mice have been kindled, the test substance is administeredeither i.p. or p.o. and, at the previously determined TPE, each animalis given the electrical stimulus indicated above. Following stimulation,the animals are observed for the presence or absence of the rearing andfalling criteria of a Stage 5 seizure. Treated animals not displaying aStage 3, 4, or 5 seizure are considered protected. The dose of the testsubstance is varied between the limits of 0 and 100% efficacy, and theED50 and 95% confidence intervals calculated by probit analysis. Meanvalues and the S.E.M. are calculated for the length of clonus andseizure duration and p values are determined by the Student's t-test.

Exemplary compounds of the application were effective in this model. Forexample, compound I(B) produced a dose related suppression of fullykindled (stage 5) seizures compared to vehicle controls withED₅₀=118.66±1.81 mg/kg (see following Table 6):

TABLE 6 Dose Individual Average (mg/kg) N/F(1) Seizure Scores Seizure 350/8 5, 5, 5, 5, 5, 5, 5, 5 5 70 1/8 5, 5, 5, 5, 5, 5, 5, 2 4.6 140 5/80, 0, 5, 0, 1, 5, 5, 3 2.4 300 8/8 0, 0, 0, 3, 3, 0, 0, 0 0.8 (1)Numberof animals active over the number tested

Example 9: Model of Mesial Temporal Lobe Epilepsy (mTLE), Mouse

The MTLE mouse model recapitulates many of the characteristics observedin human patients with temporal lobe epilepsy (TLE). The MTLE mouse ischaracterized by an initial neurotoxic event, a unilateralintrahippocampal injection of kainic acid (KA) into the dorsalhippocampus, which induces non-convulsive SE lasting several hours. Thisinitial event is followed by a latent phase. Two to three weeks after KAinjection, spontaneous recurrent hippocampal paroxysmal discharges (HPD)are only recorded in the epileptic hippocampus and remain stable andstereotyped for the whole life of the animal. These HPDs occurspontaneously about 30-60 times per hour when the animals are in a stateof quiet wakefulness, generally last 15-20 sec and are associated withbehavioral arrest and/or mild motor automatisms. Adult, male 057/B16mice are stereotaxically injected with kainate (1 nmol in 100 nL) andimplanted with 1 bipolar electrode in the dorsal hippocampus, and thenallowed to recover for four weeks prior to evaluation in the screeningprotocol. Using a group size of 4 MTLE mice per dose of investigationalcompound, the compounds are typically first tested using the 6 Hz 44 mAED50 value. If a compound demonstrates efficacy at this dose, the dosecan then be increased depending on other relevant factors; i.e., theknown TD50, to vary the protection observed. For all acute studies, drugconditions are counter-balanced in MTLE mice over a two week periodusing a Latin square dosing protocol. Animals are used as their owncontrols. Digital EEG recordings are performed on freely moving animalsfor 20 minutes pre-injection (reference period) and 90 minutespost-injection. Data are analyzed for the period of 10 minutes beforeand 10 minutes after peak time of effect of the investigationalcompound, as determined from the 6 Hz 44 mA seizure test. The effects ofthe injected compound are compared to the reference period. Anyaccompanying effect on animal behavior is noted. Data are presented asthe raw number of HPDs during the analyzed 20 min period (10 minutesbefore and 10 minutes after peak time of effect of compound) for eachMTLE mouse, group mean number of HPDs, and effect on suppression asrepresented by percent of baseline HPD values.

Exemplary compounds of the application were effective in this model. Forexample, at a dose of 125 mg/kg compound I(B) was found to be effectiveagainst spontaneous recurrent hippocampal paroxysmal discharges (HPD) inmice previously lesioned with a unilateral intrahippocampal injection ofkainic acid (KA) (see following Table 7 and FIG. 1).

TABLE 7 Table 7: Effect of Example I(B) (80-160 mg/kg) vs. keppra (600mg/kg) on Hippocampal Paroxysmal Discharges (HPD) in Mice 4 Weeks afterUnilateral Intra-hippocampal KA Injection. Dose Mean HPD Effect (% SEM(% of Compound (mg/kg) Counts baseline) baseline) I(B) 160 23.8 100 11.44.25 17.9 I(B) 80 17.3 100 15.0 7.25 42.0 Levetiracetam 600 20.8 10016.2 (Keppra) 14.3 68.7

Example 10: Mouse Formalin Test (Pain Indication)

The formalin test is performed according to the method of Tjolsen et al.Pain, 1992. 51(1). An injection of 0.5% formalin (Sigma) is made intothe planter region of the right hind paw of an adult (26-30 g) male CF-1mouse. Sub-dermal formalin injection elicits a distinct behavioralprofile characterized by the mouse licking the affected paw. Thebehavior is characteristically biphasic in nature. For example,immediately following the injection the mouse licks the paw intenselyfor approximately 10 min. This is referred to as phase 1 (or, the acutephase) and is followed by a brief latent period (<5 minutes) where thereis little behavioral activity. A more prolonged period of about 20-30min of activity then ensues, which constitutes phase 2 (or, theinflammatory phase). Prior to the administration of the investigationaldrug or vehicle, each mouse undergoes a 15-min conditioning period inone of several 6″ tall plexiglass tubes (4″ diameter) that are placed infront of a mirror. It is in these tubes that mice are later observed forthe licking activity for the duration of the experiment. Following theconditioning, the test substance is administered i.p. in a doseequivalent to the MES ED50 and the mouse returned to its home tube. Atthe TPE of the drug, the formalin is injected sub-dermally into theplantar surface of the right hind foot. It is given in a volume of 20|4,1 with a 27 gauge stainless steel needle attached to a Hamiltonsyringe. The bevel of the needle is placed facing down toward the skinsurface. Following the injection of the formalin each animal is observedfor the first 2 min of 5-min epochs until 45 min have elapsed since theadministration of the test drug. The cumulative length of licking foreach 2-min time period is measured. An animal receiving the equivalentvolume of vehicle is alienated with each mouse given the test drug (n=8,per group). Animals are humanely euthanized by CO₂ inhalationimmediately following the conclusion of the experiment. The area underthe curve (AUG) is calculated for both the acute and inflammatory phasesof the licking response for individual animals in both the test andcontrol groups. The percent of control AUG for drug-treated animalgroups is determined using the Graph-Pad Prism Version 3.03. The totalAUG for each phase of the test group is also calculated and converted topercentage of total AUG of control for each phase. The average andS.E.M. for both the drug treated and control percentages are calculatedand tested for significant difference. An effect is consideredsignificantly different from the control is p<0.05.

Exemplary compounds of the application were effective in significantlyreducing the nociceptive responses, particularly during the second phaseof formalin test. For example, compound I(B) at dose 41 mg/kg by i.p.route produced a significant decrease in the number of paw licks. Thiseffect was most pronounced in the second (late) phase as defined by the% inhibition compared to vehicle controls.

Example 11: Sciatic Ligation Model in Rats (Neuropathic Pain)

Partial Ligation of the Sciatic Nerve:

Animals will be anesthetized with sodium pentobarbital and the depth ofanesthesia monitored by their response to a tail pinch and observationof the depth of respiration. Sterile technique will be used throughoutthe surgery. The upper thigh will be shaved and wiped off with ethanoland betadine. A small incision will then be made in the skin. Theunderlying muscle of the upper thigh will be separated and the sciaticnerve exposed. The nerve is separated from the surrounding connectivetissue and slightly elevated by a pair of fine, curved forceps.Approximately ⅓ to ½ of the nerve is tied off by passing a needle (7.0)and nylon suture through the nerve. The muscle and skin incision areclosed off separately with 5.0 suture and the animals kept warm untilthey have recovered from the anesthesia. This procedure is routinelydone on the right side (ipsilateral) while a sham surgery is performedon the left hind leg (contralateral). The latter involves a similarprocedure with the exception that the sciatic nerve on this side is onlyexposed. The rats will be closely monitored daily for the development ofinfection or untoward effects of the surgery in which case the animalswill be immediately euthanized.

After an appropriate time for recovery (7 days) the animals will betested for the development of mechanical allodynia (abnormal response toa non-noxious stimulus). The animals are each put in a bottomlessplexiglass box placed on a wire mesh (¼″) platform. After 30-60 minutesin which to acclimate, a baseline mechanical sensitivity is determined.This procedure is done by applying a series of calibrated Von Freyfibers perpendicularly to the plantar surface of each hind paw andholding it there for about 6 sees with enough force to slightly bend thefiber. After a positive response (withdrawal of the foot) is noted aweaker fiber is applied. This is repeated until a 50% threshold forwithdrawal can be determined.

The allodynic threshold is then redetermined after intraperitonealadministration of an investigational AED. Testing will be conducted atthe time-to-peak effect of the AED as determined in the acute seizuremodel (Z. Seltzer et al. Pain 43 1990, 205-218).

Exemplary compounds of the application were effective in significantlyreducing the nociceptive responses, particularly during the second phaseof formalin test. For compound I(B) (60 mg/kg i.p.) produced asignificant decrease in the mechanical allodynia compared to vehiclecontrols.

Example 12: Spinal Nerve Injury (SNI) Model (Neuropathic Pain)

The SNI model of neuropathic pain was developed in rats using theprocedure described by Decostered and Woolf, Pain 2000, 87: 149-158.Under isoflurane anesthesia, the skin on the lateral surface of thethigh was incised and a section was made directly through the bicepsfemoris muscle exposing the sciatic nerve and its three terminalbranches: the sural, common peroneal and tibial nerves. The commonperoneal and the tibial nerves were tight-ligated with 6-0 suture andsectioned distal to the ligation, removing 2-4 mm of the distal nervestump. Extreme care was taken to avoid any contact with or stretching ofthe intact sural nerve. Following surgery, hemostasis was confirmed andthe muscles were sutured in layers using 4-0 suture and the skin wasclosed with 4-0 suture and metal clips.

Male, Sprague-Dawley rats were used. Testing of compounds was done 21days post-operatively. After initial basal readings were taken, the testcompound or vehicle was administered. The readings were taken again 30,60 and 180 min after the compound/vehicle administration. Both thecontrol (uninjured) and the SNI paw were tested. The presence ofmechanical allodynia was assessed using the Dynamic PlantarAesthesiometer (Ugo Basile, Italy) which is a modified version of theVon Frey Hair test. In this, a test filament is positioned below theanimal's hind paw and the unit is activated which causes the filament tomove up and touch the plantar surface of the hind paw. Increasing forceis applied to the paw via the filament. When the animal withdraws itspaw, the unit is inactivated automatically and the threshold forcerequired to elicit the paw withdrawal is displayed. A single reading wastaken per timepoint. The cut-off force was set at 50 g. The tests weredone on both the non-injured (control) and the injured (SNI) paw. Pilotstudies showed the presence of mechanical allodynia 7 days after thesurgery and lasted up to 4 weeks (end of the test period).

Cold allodynia was assessed by using the acetone test. In this test, 25μl of acetone is sprayed on to the plantar surface of the hind paw.Evaporation of acetone causes cooling of the skin. The cold stimulussets up nociceptive responses from the injured paw as evidenced by pawlifting, paw licking and grooming. The duration of the nociceptiveresponses is noted. Similar stimulus to the uninjured (control) pawusually does not elicit nociceptive responses.

In the case of the SNI model (Von Frey Hair test), the maximum reversalpossible was computed as Percent Maximum Possible Effect (MPE) (e.g.Stohr et al, Eur. J. Pharmacol. 2006, 10: 241-249).

In the SNI model of neuropathic pain, compound I(B) at a dose of 60mg/kg i.p. was effective at reducing the mechanical allodynia evident inthe denervated paw as measured using the Von Frey test. Cold allodyniain the neuropathic rats was also significantly reduced by this compound.

While the present application has been described with reference toexamples, it is to be understood that the scope of the claims should notbe limited by the embodiments set forth in the examples, but should begiven the broadest interpretation consistent with the description as awhole.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. Where a term in the present application is found to bedefined differently in a document incorporated herein by reference, thedefinition provided herein is to serve as the definition for the term.

1. A compound of Formula (I), or a pharmaceutically acceptable salt,solvate, tautomer or optical isomer, or combination thereof:

wherein: R₁ is selected from the group consisting of C₁-C₆ lower alkyl,C₁-C₆ lower alkoxy, C₁-C₆ lower alkyl-ester, C₁-C₆ lower alkyl-amide,C₁-C₆ lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆-lower haloalkoxy,C₁-C₆-lower haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl,alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl,hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl,alkynyl, aryl-alkynyl, cycloalkenyl, heterocycloalkenyl,alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,and alkylene-O-alkylene-cycloalkyl,alkylene-O-alkylene-heterocycloalkyl, each R₁ group being optionallysubstituted with one or more independently-selected groups R₅; R₂ and R₃are each independently selected from the group consisting of hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; or R₂and R₃ connect to form, together with the carbon atom to which they areattached, a three to seven-membered carbocyclic or heterocyclic ring;and R₄ is selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; X and Q are independently selected from CH₂,O, NR₇, S, SO and SO₂; R₅ is selected from the group consisting ofhydroxy, halogen, cyano, nitro, CO₂R₆, CONHR₆, CON(R₆)₂, SO₂NHR₆,SO₂N(R₆)₂, C₁-C₆ lower alkyl, C₁-C₆ lower alkoxy, C₁-C₆ loweralkyl-ester, C₁-C₆ lower alkyl-amide, C₁-C₆ lower alkyl-acid, C₁-C₆lower haloalkyl, C₁-C₆ lower haloalkoxy, C₁-C₆ lower haloalkyl-ester,cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl,heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl,cyanoalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl,alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl,alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl,alkylene-O-alkylene-cycloalkyl and alkylene-O-alkylene-heterocycloalkyl;and R₆ and R₇ are independently selected from the group consisting of H,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl,provided that at least one of R₁, R₂ and R₃ comprises a fluorine atom.2. (canceled)
 3. (canceled)
 4. (canceled)
 5. The compound of claim 1,wherein R₁ is selected from the group consisting of aryl, heteroaryl,C₁-C₆alkylene-aryl and C₁-C₆alkylene-heteroaryl, each R₁ group beingoptionally substituted with one to three independently-selected groupsR₅, wherein R₅ is selected from the group consisting of hydroxy,halogen, cyano, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₁-C₆hydroxyalkyl, C₁-C₆cyanoalkyl, andC₁-C₆alkylene-O—C₁-C₆alkyl.
 6. (canceled)
 7. (canceled)
 8. The compoundof claim 1, wherein R₁ is C₁-C₄alkylene-aryl optionally substituted withone R₅ group, wherein R₅ is selected from the group consisting of Cl, F,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkyl and C₁-C₄fluoroalkoxy. 9.(canceled)
 10. The compound of claim 8, wherein the R₅ group is locatedat the para position.
 11. (canceled)
 12. The compound of claim 1,wherein R₂ and R₃ are each independently selected from the groupconsisting of hydrogen, Cl, F, C₁-C₄alkyl and C₁-C₄haloalkyl. 13.(canceled)
 14. The compound of claim 12, wherein R₂ and R₃ are both H orare both F, or one of R₂ and R₃ is H and the other is F.
 15. (canceled)16. The compound of claim 1, wherein R₄ is selected from the groupconsisting of hydrogen, C₁-C₄alkyl and C₁-C₄haloalkyl.
 17. The compoundof claim 16, wherein R₄ is selected from the group consisting ofhydrogen and CH₃.
 18. (canceled)
 19. The compound of claim 1, wherein Xand Q are independently selected from O and NR₇, wherein R₇ is selectedfrom the group consisting of hydrogen, C₁-C₄alkyl and C₁-C₄haloalkyl.20. The compound of claim 19, wherein X and Q are independently selectedfrom O and NR₇, wherein R₇ is selected from the group consisting ofhydrogen and CH₃.
 21. The compound of claim 1, wherein X is O.
 22. Thecompound of claim 20, wherein Q is selected from O and NR₇.
 23. Thecompound of claim 1, wherein Q is O.
 24. The compound of claim 1,wherein R₆ is selected from the group consisting of hydrogen andC₁-C₄alkyl.
 25. The compound of claim 1, wherein R₁ comprises adifluoromethoxy or a trifluoromethoxy substituent.
 26. The compound ofclaim 1, wherein R₂ and R₃ are both F.
 27. The compound of claim 1,selected from: 7-benzyloxy-4H benzo[1,4]oxazin-3-one;7-(4-fluoro-benzyloxy)-4H-benzo[1,4]oxazin-3-one;7-(4-difluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one;7-(4-trifluoromethoxy-benzyloxy)-4H-benzo[1,4]oxazin-3-one; and7-benzyloxy-2,2-difluoro-4H-benzo[1,4]oxazin-3-one; or apharmaceutically-acceptable salt, solvate, tautomer or optical isomer,or combination thereof.
 28. A compound of the formula:

or a pharmaceutically-acceptable solvate or tautomer, or combinationthereof.
 29. A pharmaceutical composition comprising a compoundaccording to claim 1 and at least one pharmaceutically acceptablecarrier and/or excipient.
 30. A method for treating at least one ofepilepsy, neuropathic pain, acute and chronic inflammatory pain,migraine, tardive dyskinesia, anxiety and other related CNS disorders ina mammal, comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim
 1. 31. (canceled) 32.(canceled)